{
"data": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "001_BP6",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"instructionsToUse": "",
"label": "BP6",
"ns": "001",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432758",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432758",
"modified": "2022-08-18T15:51:42.897Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxou--C"
},
{
"entContent": {
"_uniqueProp": "001_PP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"label": "PP2",
"ns": "001",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639550",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639550",
"modified": "2022-08-18T15:51:42.290Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--G"
},
{
"entContent": {
"_uniqueProp": "001_PS1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"label": "PS1",
"ns": "001",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639539",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639539",
"modified": "2022-08-18T15:51:41.169Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxou--B"
},
{
"entContent": {
"_uniqueProp": "001_PM5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"label": "PM5",
"ns": "001",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639535",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639535",
"modified": "2022-08-18T15:51:40.711Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--G"
},
{
"entContent": {
"_uniqueProp": "001_PM3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"label": "PM3",
"ns": "001",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639531",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639531",
"modified": "2022-08-18T15:51:40.223Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxou--A"
},
{
"entContent": {
"_uniqueProp": "001_PP5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"instructionsToUse": "",
"label": "PP5",
"ns": "001",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432759",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432759",
"modified": "2022-08-18T15:51:42.988Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--H"
},
{
"entContent": {
"_uniqueProp": "001_PM2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"label": "PM2",
"ns": "001",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639555",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639555",
"modified": "2022-08-18T15:51:42.790Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--L"
},
{
"entContent": {
"_uniqueProp": "001_BA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"label": "BA1",
"ns": "001",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639549",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639549",
"modified": "2022-08-18T15:51:42.199Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--J"
},
{
"entContent": {
"_uniqueProp": "001_BP5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"label": "BP5",
"ns": "001",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639548",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639548",
"modified": "2022-08-18T15:51:42.110Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--J"
},
{
"entContent": {
"_uniqueProp": "001_BP4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"label": "BP4",
"ns": "001",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639544",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639544",
"modified": "2022-08-18T15:51:41.682Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--F"
},
{
"entContent": {
"_uniqueProp": "001_PS2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"label": "PS2",
"ns": "001",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639541",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639541",
"modified": "2022-08-18T15:51:41.354Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--I"
},
{
"entContent": {
"_uniqueProp": "001_BS4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"label": "BS4",
"ns": "001",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639537",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639537",
"modified": "2022-08-18T15:51:40.973Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--I"
},
{
"entContent": {
"_uniqueProp": "001_PM1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"label": "PM1",
"ns": "001",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639554",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639554",
"modified": "2022-08-18T15:51:42.696Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo2--_"
},
{
"entContent": {
"_uniqueProp": "001_PS4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"label": "PS4",
"ns": "001",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639546",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639546",
"modified": "2022-08-18T15:51:41.876Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--L"
},
{
"entContent": {
"_uniqueProp": "001_PP1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"label": "PP1",
"ns": "001",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639545",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639545",
"modified": "2022-08-18T15:51:41.780Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--K"
},
{
"entContent": {
"_uniqueProp": "001_PS3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"label": "PS3",
"ns": "001",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639543",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639543",
"modified": "2022-08-18T15:51:41.578Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--D"
},
{
"entContent": {
"_uniqueProp": "001_PM6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"label": "PM6",
"ns": "001",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639538",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639538",
"modified": "2024-07-23T12:25:59.751Z",
"modifier": "cspecAdministrator",
"rev": "_iL8MNrm---"
},
{
"entContent": {
"_uniqueProp": "001_PP4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"label": "PP4",
"ns": "001",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639553",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639553",
"modified": "2022-08-18T15:51:42.596Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--K"
},
{
"entContent": {
"_uniqueProp": "001_PP3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"label": "PP3",
"ns": "001",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639551",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639551",
"modified": "2022-08-18T15:51:42.410Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo2---"
},
{
"entContent": {
"_uniqueProp": "001_PVS1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"label": "PVS1",
"ns": "001",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639547",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639547",
"modified": "2022-08-18T15:51:41.976Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--I"
},
{
"entContent": {
"_uniqueProp": "001_BP3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"label": "BP3",
"ns": "001",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639542",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639542",
"modified": "2022-08-18T15:51:41.476Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--H"
},
{
"entContent": {
"_uniqueProp": "001_BP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"label": "BP2",
"ns": "001",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639540",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639540",
"modified": "2022-08-18T15:51:41.259Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--J"
},
{
"entContent": {
"_uniqueProp": "001_BS3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"label": "BS3",
"ns": "001",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639534",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639534",
"modified": "2022-08-18T15:51:40.606Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--A"
},
{
"entContent": {
"_uniqueProp": "001_PM4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"label": "PM4",
"ns": "001",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639533",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639533",
"modified": "2022-08-18T15:51:40.472Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--H"
},
{
"entContent": {
"_uniqueProp": "001_BS2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"label": "BS2",
"ns": "001",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639532",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639532",
"modified": "2022-08-18T15:51:40.365Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--G"
},
{
"entContent": {
"_uniqueProp": "001_BP7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"label": "BP7",
"ns": "001",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639552",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639552",
"modified": "2022-08-18T15:51:42.501Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--K"
},
{
"entContent": {
"_uniqueProp": "001_BP1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"label": "BP1",
"ns": "001",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639536",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639536",
"modified": "2022-08-18T15:51:40.839Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--C"
},
{
"entContent": {
"_uniqueProp": "001_BS1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"label": "BS1",
"ns": "001",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is greater than expected for disorder.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639530",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639530",
"modified": "2022-08-18T15:51:40.085Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxoy--G"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "001",
"ns": "001",
"rules": {
"mainRules": [
{
"conditions": [
{
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule21, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule21, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule21"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule22, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule22"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule23, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule23, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule23"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule24, Condition1",
"partitionPath": "Benign.Strong"
},
{
"condition": ">=1",
"label": "Rule24, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule24"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule25, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule25, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule25"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule26, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule26, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule26"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule27, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule27, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule27"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule28, Condition1",
"partitionPath": "Benign.Stand Alone"
},
{
"condition": ">=1",
"label": "Rule28, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule28"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule29, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule29, Condition2",
"partitionPath": "Pathogenic.Very Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule29"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule30, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule30, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule30"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule31, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule31, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule31"
},
{
"conditions": [
{
"condition": ">=1",
"label": "Rule32, Condition1",
"partitionPath": "Benign.Supporting"
},
{
"condition": ">=1",
"label": "Rule32, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Uncertain Significance - Conflicting Evidence",
"rule": "Rule32"
}
],
"metaRules": [
{
"description": "Given set of evidence are not sufficient to make any assertions.",
"inference": "Uncertain Significance - Insufficient Evidence",
"metaRule": "MetaRule1",
"numberOfAssertions": 0,
"uniqueAssertions": []
},
{
"description": "As the rules only suggest one assertion that is Pathogenic, the final assertion is Pathogenic",
"inference": "Pathogenic",
"metaRule": "MetaRule2",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Pathogenic"
]
},
{
"description": "As the rules only suggest one assertion that is Benign, the final assertion is Benign",
"inference": "Benign",
"metaRule": "MetaRule3",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Benign"
]
},
{
"description": "As the rules only suggest one assertion that is Likely Pathogenic, the final assertion is Likely Pathogenic",
"inference": "Likely Pathogenic",
"metaRule": "MetaRule4",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Likely Pathogenic"
]
},
{
"description": "As the rules only suggest one assertion that is Likely Pathogenic, the final assertion is Likely Benign",
"inference": "Likely Benign",
"metaRule": "MetaRule5",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Likely Benign"
]
},
{
"description": "As the rules only suggest one assertion that is Uncertain Significance - Conflicting Evidence - Insufficient Evidence, the final assertion is Uncertain Significance - Conflicting Evidence - Insufficient Evidence",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule6",
"numberOfAssertions": 1,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Two assertions: Pathogenic and Likely Pathogenic were made. In such case the final call is the highest strength call, hence the allele is Pathogenic",
"inference": "Pathogenic",
"metaRule": "MetaRule7",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic"
]
},
{
"description": "Two assertions: Benign and Likely Benign were made. In such case the final call is the highest strength call, hence the allele is Benign",
"inference": "Benign",
"metaRule": "MetaRule8",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Benign",
"Likely Benign"
]
},
{
"description": "Three assertions: Pathogenic, Likely Pathogenic and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule9",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Three assertions: Benign, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule10",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Benign",
"Likely Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Two assertions: Pathogenic and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule11",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic"
]
},
{
"description": "Two assertions: Likely Pathogenic and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule12",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic"
]
},
{
"description": "Two assertions: Benign and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule13",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Benign"
]
},
{
"description": "Two assertions: Likely Benign and Uncertain Significance - Conflicting Evidence were made. The final call in this case is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule14",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Benign"
]
},
{
"description": "Three assertions: Likely Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule15",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Pathogenic",
"Likely Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Three assertions: Likely Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule16",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "Three assertions: Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule17",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic",
"Likely Benign"
]
},
{
"description": "Three assertions: Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule18",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Benign",
"Uncertain Significance - Conflicting Evidence"
]
},
{
"description": "Four assertions: Likely Pathogenic, Pathogenic, Likely Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule19",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Likely Benign",
"Pathogenic"
]
},
{
"description": "Four assertions: Likely Pathogenic, Pathogenic, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule20",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Pathogenic",
"Benign"
]
},
{
"description": "Four assertions: Likely Pathogenic, Likely Benign, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule21",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Likely Pathogenic",
"Likely Benign",
"Benign"
]
},
{
"description": "Four assertions: Pathogenic, Likely Benign, Benign and Uncertain Significance - Conflicting Evidence were made. In such cases the final call is Uncertain Significance - Conflicting Evidence.",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule22",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Uncertain Significance - Conflicting Evidence",
"Pathogenic",
"Likely Benign",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule27",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule28",
"numberOfAssertions": 2,
"uniqueAssertions": [
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule34",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule35",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Likely Benign",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule37",
"numberOfAssertions": 3,
"uniqueAssertions": [
"Pathogenic",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule44",
"numberOfAssertions": 4,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Likely Pathogenic",
"Benign"
]
},
{
"description": "",
"inference": "Uncertain Significance - Conflicting Evidence",
"metaRule": "MetaRule23",
"numberOfAssertions": 5,
"uniqueAssertions": [
"Likely Benign",
"Pathogenic",
"Likely Pathogenic",
"Uncertain Significance - Conflicting Evidence",
"Benign"
]
}
],
"pointRules": [
{
"conditions": [
{
"condition": ">=10",
"label": "Rule1, Condition1"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"condition": ">=6",
"label": "Rule2, Condition2"
},
{
"condition": "<=9",
"label": "Rule2, Condition1"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"condition": ">=0",
"label": "Rule3, Condition1"
},
{
"condition": "<=5",
"label": "Rule3, Condition2"
}
],
"inference": "Uncertain Significance",
"rule": "Rule3"
},
{
"conditions": [
{
"condition": ">=-6",
"label": "Rule4, Condition1"
},
{
"condition": "<=-1",
"label": "Rule4, Condition2"
}
],
"inference": "Likely Benign",
"rule": "Rule4"
},
{
"conditions": [
{
"condition": "<=-7",
"label": "Rule5, Condition1"
}
],
"inference": "Benign",
"rule": "Rule5"
}
]
}
},
"entType": "RuleSet",
"ldhId": "135641113",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641113",
"modified": "2025-02-28T14:16:01.154Z",
"modifier": "cspecAdministrator",
"rev": "_jSxoAYi---"
}
],
"SequenceVariantInterpretation": [
{
"created": "2025-12-08T15:45:37.420Z",
"creator": "devScorer",
"entContent": {
"description": "Test",
"namespace": "GN176",
"releaseNotes": "",
"shortTitle": "ACADVL Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "devScorer",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2025-12-08T15:45:28.614Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"176"
],
"title": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BBC3 Version 1.0.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.0.0",
"versioned": true
},
"entId": "GN176",
"entType": "SequenceVariantInterpretation",
"ldhId": "2733280882",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/2733280882",
"modified": "2025-12-08T15:45:37.420Z",
"modifier": "devScorer",
"rev": "_kt4hvqC---"
},
{
"created": "2025-05-20T16:18:34.204Z",
"creator": "devScorer",
"entContent": {
"description": "Test",
"namespace": "GN174",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "devScorer",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2025-05-20T16:18:26.926Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"174"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CGA Version 1.0.0",
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015",
"version": "1.0.0",
"versioned": true
},
"entId": "GN174",
"entType": "SequenceVariantInterpretation",
"ldhId": "2363240640",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/2363240640",
"modified": "2025-05-20T16:18:34.204Z",
"modifier": "devScorer",
"rev": "_js37UFq---"
},
{
"created": "2024-03-15T12:11:02.030Z",
"creator": "coraleas",
"entContent": {
"description": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"namespace": "GN172",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-03-15T12:10:58.314Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"172"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN172",
"entType": "SequenceVariantInterpretation",
"ldhId": "1745678696",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1745678696",
"modified": "2024-03-15T12:11:02.030Z",
"modifier": "coraleas",
"rev": "_h6SHykG--h"
},
{
"created": "2024-01-09T17:04:19.767Z",
"creator": "leekristy",
"entContent": {
"description": "This VCEP is only curating the ABCA4 gene with a single autosomal recessive phenotype, which is ABCA4-related retinopathies.",
"namespace": "GN164",
"releaseNotes": "",
"shortTitle": "ABCA4 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-01-09T17:04:14.791Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2025-09-04T17:37:14.016Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-01-16T19:00:52.694Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-02-21T17:38:39.143Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"164"
],
"title": "ClinGen ABCA4 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCA4 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN164",
"entType": "SequenceVariantInterpretation",
"ldhId": "1670130991",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1670130991",
"modified": "2025-09-04T17:37:14.349Z",
"modifier": "cspecAdministrator",
"rev": "_kPVLylq--A"
},
{
"created": "2023-12-11T19:18:59.444Z",
"creator": "placee",
"entContent": {
"description": "",
"namespace": "GN162",
"releaseNotes": "",
"shortTitle": "Ocular Anterior Segment Disorder Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-12-11T19:18:55.562Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-01-12T20:59:31.954Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-01-12T20:53:38.915Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-01-25T20:51:29.938Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"162"
],
"title": "ClinGen Ocular Anterior Segment Disorder Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAX6 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN162",
"entType": "SequenceVariantInterpretation",
"ldhId": "1628062275",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1628062275",
"modified": "2024-01-25T20:51:30.234Z",
"modifier": "sharriso",
"rev": "_h6SHykG--d"
},
{
"created": "2023-11-28T12:20:17.547Z",
"creator": "mweaver",
"entContent": {
"description": "ACADVL VCEP specifications v1.1",
"namespace": "GN161",
"releaseNotes": "",
"shortTitle": "ACADVL Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-11-28T12:20:13.706Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-11-28T12:40:43.234Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-11-30T14:42:21.046Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "cspec-deleted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-01-25T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"161"
],
"title": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACADVL Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN161",
"entType": "SequenceVariantInterpretation",
"ldhId": "1626639399",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1626639399",
"modified": "2024-01-25T19:42:46.112Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykW--B"
},
{
"created": "2023-11-27T19:42:21.202Z",
"creator": "alejandronietopatlan",
"entContent": {
"description": "PIK3R1",
"namespace": "GN160",
"releaseNotes": "",
"shortTitle": "Antibody Deficiencies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-11-27T19:42:17.865Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-11-27T21:58:07.224Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-01-18T19:59:14.881Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"160"
],
"title": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN160",
"entType": "SequenceVariantInterpretation",
"ldhId": "1626566541",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1626566541",
"modified": "2024-01-18T19:59:15.221Z",
"modifier": "tsneddon",
"rev": "_h6SHyk---J"
},
{
"created": "2023-11-13T13:33:12.920Z",
"creator": "mweaver",
"entContent": {
"description": "GALT gene specifications",
"namespace": "GN158",
"releaseNotes": "",
"shortTitle": "Galactosemia Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-11-13T13:33:09.266Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-01-22T10:28:36.745Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-03-25T21:20:40.478Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"158"
],
"title": "ClinGen Galactosemia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GALT Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN158",
"entType": "SequenceVariantInterpretation",
"ldhId": "1624749084",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1624749084",
"modified": "2024-03-25T21:20:40.784Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyk---T"
},
{
"created": "2023-10-26T09:39:20.930Z",
"creator": "mweaver",
"entContent": {
"description": "Ornithine Carbamoyltransferase (OTC) specifications",
"namespace": "GN156",
"releaseNotes": "",
"shortTitle": "Urea Cycle Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-10-26T09:39:17.357Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-03-22T15:08:07.197Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-03-11T15:42:15.126Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"156"
],
"title": "ClinGen Urea Cycle Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTC Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN156",
"entType": "SequenceVariantInterpretation",
"ldhId": "1622722963",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1622722963",
"modified": "2024-03-22T15:08:07.356Z",
"modifier": "mweaver",
"rev": "_h6SHykG--L"
},
{
"entContent": {
"description": "",
"namespace": "GN150",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-08-30T18:35:10.353Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-11T01:53:12.182Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-01T17:46:23.503Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-03T23:35:11.515Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"150"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN150",
"entType": "SequenceVariantInterpretation",
"ldhId": "1616389153",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1616389153",
"modified": "2024-03-11T01:53:12.327Z",
"modifier": "mtdistefano",
"rev": "_h6SHykW--L"
},
{
"entContent": {
"description": "",
"namespace": "GN147",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-08-21T15:47:38.991Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-04T03:06:22.784Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-04T03:04:59.956Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-03T23:34:30.842Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"147"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN147",
"entType": "SequenceVariantInterpretation",
"ldhId": "1615403520",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1615403520",
"modified": "2024-03-04T03:06:22.933Z",
"modifier": "mtdistefano",
"rev": "_h6SHykW--I"
},
{
"entContent": {
"namespace": "GN144",
"releaseNotes": "",
"shortTitle": "Parkinson's Disease Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "shilpacrao",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-26T19:21:54.238Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"144"
],
"title": "ClinGen Parkinson's Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LRRK2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN144",
"entType": "SequenceVariantInterpretation",
"ldhId": "1612839626",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1612839626",
"modified": "2023-07-26T19:21:58.540Z",
"modifier": "shilpacrao",
"rev": "_h6SHykG--C"
},
{
"entContent": {
"namespace": "GN133",
"releaseNotes": "",
"shortTitle": "Hereditary Angioedema Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "marwa_elnagheeb",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-02T13:24:26.771Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"133"
],
"title": "ClinGen Hereditary Angioedema Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPING1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN133",
"entType": "SequenceVariantInterpretation",
"ldhId": "1575651794",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1575651794",
"modified": "2023-06-02T13:24:30.287Z",
"modifier": "marwa_elnagheeb",
"rev": "_h6SHyj6--M"
},
{
"entContent": {
"namespace": "GN132",
"releaseNotes": "",
"shortTitle": "Amyotrophic Lateral Sclerosis Spectrum Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "marwa_elnagheeb",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-02T13:21:06.508Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"132"
],
"title": "ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOD1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN132",
"entType": "SequenceVariantInterpretation",
"ldhId": "1575650622",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1575650622",
"modified": "2023-06-02T13:21:10.784Z",
"modifier": "marwa_elnagheeb",
"rev": "_h6SHykS--D"
},
{
"entContent": {
"namespace": "GN130",
"releaseNotes": "",
"shortTitle": "Kidney Cystic and Ciliopathy Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "proberts",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-05-10T14:30:26.782Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"130"
],
"title": "ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN130",
"entType": "SequenceVariantInterpretation",
"ldhId": "1572289348",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1572289348",
"modified": "2023-05-10T14:30:30.321Z",
"modifier": "proberts",
"rev": "_h6SHyjy--C"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:41:21.808Z",
"description": "",
"namespace": "GN124",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-29T17:12:51.898Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:51:17.223Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:15:32.976Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:46:26.523Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:41:21.808Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"124"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN124",
"entType": "SequenceVariantInterpretation",
"ldhId": "1567863456",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567863456",
"modified": "2023-10-09T11:41:22.351Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--Z"
},
{
"entContent": {
"description": "",
"namespace": "GN122",
"releaseNotes": "",
"shortTitle": "Antibody Deficiencies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-22T15:55:11.275Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-03-28T16:43:51.161Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-29T18:38:35.613Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-03-31T17:02:06.115Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-31T16:46:54.918Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-17T16:05:04.520Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"122"
],
"title": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CTLA4 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN122",
"entType": "SequenceVariantInterpretation",
"ldhId": "1567102241",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567102241",
"modified": "2023-05-17T16:05:04.848Z",
"modifier": "tsneddon",
"rev": "_h6SHykS--C"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:38:46.020Z",
"description": "",
"namespace": "GN119",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-15T15:11:40.068Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-03-30T16:37:33.282Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-30T16:34:58.280Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:49:35.085Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:12:32.622Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:44:08.497Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:38:46.020Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"119"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL7R Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN119",
"entType": "SequenceVariantInterpretation",
"ldhId": "1566364238",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1566364238",
"modified": "2023-10-09T11:38:46.540Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--X"
},
{
"entContent": {
"namespace": "GN118",
"releaseNotes": "",
"shortTitle": "Limb Girdle Muscular Dystrophy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "macalalad",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-10T19:55:25.783Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-07-23T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"118"
],
"title": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ANO5 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN118",
"entType": "SequenceVariantInterpretation",
"ldhId": "1565663255",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1565663255",
"modified": "2024-07-23T11:23:11.774Z",
"modifier": "cspecAdministrator",
"rev": "_iL7SuB----"
},
{
"entContent": {
"description": "",
"namespace": "GN113",
"releaseNotes": "",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-02-23T20:54:12.934Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-08-21T20:19:51.417Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-07-28T22:35:40.538Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-10-05T15:58:02.964Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-08T21:11:24.443Z"
},
"name": "Pilot Rules Submitted"
}
],
"tagNameSpaces": [
"113"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXN1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN113",
"entType": "SequenceVariantInterpretation",
"ldhId": "1562840326",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1562840326",
"modified": "2024-02-08T21:11:24.698Z",
"modifier": "mnzelnic",
"rev": "_h6SHykG--C"
},
{
"entContent": {
"description": "",
"namespace": "GN112",
"releaseNotes": "",
"shortTitle": "Potassium Channel Arrhythmia Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-02-20T15:36:11.639Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-07T19:49:31.097Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-05T17:23:25.179Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-08-25T16:46:42.658Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"112"
],
"title": "ClinGen Potassium Channel Arrhythmia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN112",
"entType": "SequenceVariantInterpretation",
"ldhId": "1562365900",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1562365900",
"modified": "2023-08-25T16:46:43.035Z",
"modifier": "sharriso",
"rev": "_h6SHykS--F"
},
{
"entContent": {
"description": "ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3",
"namespace": "GN110",
"releaseNotes": "",
"shortTitle": "PTEN Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "shengany",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-01-11T20:54:19.131Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-01-17T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"110"
],
"title": "ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN110",
"entType": "SequenceVariantInterpretation",
"ldhId": "1553964879",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1553964879",
"modified": "2023-01-27T21:47:10.678Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--G"
},
{
"entContent": {
"approvedOn": "2023-12-21T20:17:19.708Z",
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA1 and BRCA2",
"namespace": "GN097",
"releaseNotes": "Updates in v1.1:\n\nUpdated web-link for suggested co-segregation analysis tool (COOL)\n\nUpdated assigned PVS1 codes for some variants in Specifications Table 4\n\nUpdated assigned PS3/BS3 codes for some variants in Specifications Table 9, including results updates from interim Findlay report\n\nCorrected typos and errors\n\nAdded Supplementary table 16 - mRNA assay evidence used to highlight IVS1/2 variants eligible for PVS1 (RNA) code\n\nClarified code combinations table in Specifications document: any conflicting pathogenic and benign evidence codes should be resolved using approach 2 (points system)",
"releasedUnderRevision": true,
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-01T05:58:55.256Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-23T06:15:12.753Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-10T20:53:02.886Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T17:33:20.948Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-12-21T20:17:19.708Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-23T06:07:50.561Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"097"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN097",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535438831",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535438831",
"modified": "2023-12-21T20:17:20.109Z",
"modifier": "michaelP",
"rev": "_h6SHyk---H"
},
{
"entContent": {
"namespace": "GN096",
"releaseNotes": "",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-30T15:49:10.369Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"096"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN096",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535377178",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535377178",
"modified": "2022-11-30T15:49:13.920Z",
"modifier": "meganholdren",
"rev": "_h6SHyju--D"
},
{
"entContent": {
"description": "",
"namespace": "GN094",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-03T14:32:08.907Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T15:00:00.782Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-01T16:55:59.177Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-21T18:09:32.828Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:49.978Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"094"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN094",
"entType": "SequenceVariantInterpretation",
"ldhId": "1532496138",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1532496138",
"modified": "2023-09-06T21:13:50.213Z",
"modifier": "sharriso",
"rev": "_h6SHyk---_"
},
{
"entContent": {
"approvedOn": "2023-10-05T13:25:41.651Z",
"description": "Rule specifications for hemophilia B.",
"namespace": "GN080",
"releaseNotes": "Edits post SVI review",
"shortTitle": "Coagulation Factor Deficiency Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:49:44.254Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-13T15:31:23.630Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-07T15:39:45.376Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-08T23:19:54.383Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-01T16:22:13.358Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-05T13:25:41.651Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"080"
],
"title": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN080",
"entType": "SequenceVariantInterpretation",
"ldhId": "1527859052",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527859052",
"modified": "2023-10-05T13:25:42.077Z",
"modifier": "leekristy",
"rev": "_h6SHykK--B"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:38:47.541Z",
"description": "SCN1B",
"namespace": "GN076",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-12T19:49:49.841Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T20:00:33.365Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:43.650Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:34.421Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:06:05.714Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:49.182Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:29.860Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:38:47.541Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"076"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN076",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243146",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243146",
"modified": "2024-03-19T18:38:48.061Z",
"modifier": "laceysmith",
"rev": "_h6SHykK--N"
},
{
"entContent": {
"description": "",
"namespace": "GN074",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T14:02:11.437Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:35:56.462Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:36:54.577Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"074"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2B Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN074",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243144",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243144",
"modified": "2023-04-11T17:36:54.940Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--A"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:40:48.728Z",
"description": "SCN1A\n ",
"namespace": "GN067",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-25T12:32:02.290Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:56:03.778Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:34:25.209Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:24.019Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:04:23.222Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:42.792Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:22.670Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:40:48.728Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"067"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN067",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243137",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243137",
"modified": "2024-03-19T18:40:49.258Z",
"modifier": "laceysmith",
"rev": "_h6SHykG--K"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN066",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:33.937Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"066"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN066",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243136",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243136",
"modified": "2022-08-18T19:14:37.292Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--B"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN061",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:13.987Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"061"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for AKT3 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN061",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243131",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243131",
"modified": "2022-11-11T18:08:11.946Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--B"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN054",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:44.669Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"054"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO6 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN054",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243124",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243124",
"modified": "2022-08-18T19:13:48.137Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--B"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN049",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:24.322Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:18:54.826Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:18:12.960Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:05.564Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"049"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN049",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243119",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243119",
"modified": "2023-09-06T21:13:05.701Z",
"modifier": "sharriso",
"rev": "_h6SHykS--K"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN045",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:08.948Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:49:05.328Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:47:46.078Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:27.247Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"045"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN045",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243115",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243115",
"modified": "2023-09-06T21:12:27.379Z",
"modifier": "sharriso",
"rev": "_h6SHykG--F"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN041",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:53.367Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:35:43.611Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:34:23.894Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:50.393Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"041"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN041",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243111",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243111",
"modified": "2023-09-06T21:11:50.611Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN038",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:41.717Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:17:40.158Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:16:53.504Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:10.967Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"038"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN038",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243108",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243108",
"modified": "2023-09-06T21:11:11.189Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--H"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:23.860Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN037",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:36.966Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:25:24.952Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-01T12:01:42.805Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-04T16:31:30.362Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:27.074Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:23.860Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-02-09T19:15:05.530Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"037"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0",
"version": "4.0.0",
"versioned": true
},
"entId": "GN037",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243107",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243107",
"modified": "2023-09-29T15:16:49.726Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--W"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:51:04.353Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for Solute Carrier Family 6, Member 8 (SLC6A8; Creatine Transporter) Summary of ACMG-AMP Criteria for SLC6A8 Variants",
"namespace": "GN027",
"releaseNotes": "* Added PM6. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for PS2\\_Moderate.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:51:04.353Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T18:15:28.297Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2022-09-07T17:53:39.002Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:51:40.093Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:00.425Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"027"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN027",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243097",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243097",
"modified": "2023-10-11T18:15:28.510Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHyk---G"
},
{
"entContent": {
"approvedOn": "2021-11-19T00:00:00.000Z",
"description": "This version specified for the following genes: MYOC",
"namespace": "GN019",
"releaseNotes": "Added MYOC HGNC ID, Replaced disease identifiers Primary open-angle glaucoma (POAG) and juvenile onset open-angle glaucoma (JOAG) (MIM: 137750) with primary open angle glaucoma (MONDO:0007665) and juvenile open angle glaucoma (MONDO:0020367).",
"shortTitle": "Glaucoma",
"specificationSource": "https://clinicalgenome.org/docs/clingen-glaucoma-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"019"
],
"title": "ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1",
"version": "1.1.0"
},
"entId": "GN019",
"entType": "SequenceVariantInterpretation",
"ldhId": "635003679",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/635003679",
"modified": "2023-09-29T15:16:48.273Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--N"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"namespace": "GN015",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines mtDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"015"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA",
"version": "1.0.0"
},
"entId": "GN015",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637588",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637588",
"modified": "2023-09-29T15:16:47.750Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---C"
},
{
"entContent": {
"approvedOn": "2022-03-01T00:00:00.000Z",
"description": "This version specified for the following genes: RYR1",
"namespace": "GN012",
"notes": "",
"references": [
{
"source": "BioRxiv",
"url": "https://doi.org/10.1101/2020.11.29.402768"
}
],
"releaseNotes": "\n(1) Revised PS4 such that at all strength levels an individual with two VUS/LP/P variants in RYR1 cannot be considered as supporting pathogenicity of either variant.\n(2) PS1 can be used at level moderate for previously classified likely pathogenic variant at the same codon with the same amino acid change.\n(3) PM5 can be used at level supporting for previously classified likely pathogenic variant at the same codon, different amino acid change.\n(4) PM1 should be downgraded to supporting when either PS1 or PM5 are used.",
"shortTitle": "ACMG variant classification Malignant Hyperthermia",
"specificationSource": "https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"012"
],
"title": "ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2",
"version": "2.0.0"
},
"entId": "GN012",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637584",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637584",
"modified": "2023-09-29T15:16:47.385Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK---"
},
{
"entContent": {
"approvedOn": "2021-06-02T00:00:00.000Z",
"description": "LSD EP specifications to the ACMG/AMP Variant Curation Guidelines",
"namespace": "GN010",
"notes": "",
"references": [],
"releaseNotes": "\n * Specifications for PS3 and BS3 have been revised and the strength has been downgraded.\n * PM2 has been downgraded to PM2_Supporting.\n * PP4 has been revised to allow the use of additional evidence types with strength of evidence based on a points system.\n * Cases are no longer required to meet the strict PP4 criterion in order to be counted for PM3.\n * Specifications for PM1 and BS2 are now included.\n * The tools used for in silico prediction of the impact of splice variants and in frame insertions and deletions for PP3 and BP4 have been revised.",
"shortTitle": "LSD VCEP ACMG/AMP Specifications",
"specificationSource": "https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-06-02T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"010"
],
"title": "ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0"
},
"entId": "GN010",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637582",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637582",
"modified": "2023-09-29T15:16:46.069Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--I"
},
{
"created": "2024-01-12T21:03:37.485Z",
"creator": "placee",
"entContent": {
"namespace": "GN166",
"releaseNotes": "",
"shortTitle": "Optic Nerve Atrophy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "placee",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-01-12T21:03:33.719Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"166"
],
"title": "ClinGen Optic Nerve Atrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OPA1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN166",
"entType": "SequenceVariantInterpretation",
"ldhId": "1670130993",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1670130993",
"modified": "2024-01-12T21:03:37.485Z",
"modifier": "placee",
"rev": "_h6SHykW--A"
},
{
"created": "2023-11-22T23:37:09.958Z",
"creator": "taylorwalker",
"entContent": {
"description": "DDX41 draft classification rules",
"namespace": "GN159",
"releaseNotes": "",
"shortTitle": "Myeloid Malignancy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-11-22T23:37:06.363Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-11-23T01:45:21.775Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-02-06T19:37:16.547Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"159"
],
"title": "ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DDX41 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN159",
"entType": "SequenceVariantInterpretation",
"ldhId": "1625925053",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1625925053",
"modified": "2024-02-06T19:37:16.864Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHykG--B"
},
{
"created": "2023-10-16T13:37:37.011Z",
"creator": "coraleas",
"entContent": {
"description": "This version is specified for the following gene: HBA1",
"namespace": "GN155",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-10-16T13:37:33.218Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"155"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN155",
"entType": "SequenceVariantInterpretation",
"ldhId": "1621636690",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1621636690",
"modified": "2023-10-16T13:37:37.011Z",
"modifier": "coraleas",
"rev": "_h6SHykG---"
},
{
"created": "2023-09-03T22:43:14.954Z",
"creator": "tonipollin",
"entContent": {
"description": "Insulin gene variants",
"namespace": "GN151",
"releaseNotes": "",
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-09-03T22:43:11.391Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"151"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for INS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN151",
"entType": "SequenceVariantInterpretation",
"ldhId": "1616784014",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1616784014",
"modified": "2023-09-03T22:43:14.954Z",
"modifier": "tonipollin",
"rev": "_h6SHyk----"
},
{
"entContent": {
"description": "",
"namespace": "GN149",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-08-29T17:51:51.985Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-26T04:19:33.018Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-03T23:34:01.992Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-26T04:18:44.504Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"149"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTM1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN149",
"entType": "SequenceVariantInterpretation",
"ldhId": "1616197506",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1616197506",
"modified": "2024-02-26T04:19:33.138Z",
"modifier": "mtdistefano",
"rev": "_h6SHykG--F"
},
{
"entContent": {
"description": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MMR genes Version 1.0.0",
"namespace": "GN137",
"releaseNotes": "",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-23T05:39:52.992Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-08T05:59:41.483Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-18T05:31:17.886Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-12T22:23:58.391Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"137"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN137",
"entType": "SequenceVariantInterpretation",
"ldhId": "1577628936",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1577628936",
"modified": "2024-03-08T05:59:41.623Z",
"modifier": "johnplaz",
"rev": "_h6SHykW--K"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:41:57.074Z",
"description": "",
"namespace": "GN129",
"releaseNotes": "Additional variants for the IL2RG pilot phase were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-05-03T21:30:24.961Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-05-30T21:42:18.141Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-30T21:37:29.360Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-09T19:02:43.285Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-07-05T18:14:42.351Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-05T18:11:19.727Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:47:25.884Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:41:57.074Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"129"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN129",
"entType": "SequenceVariantInterpretation",
"ldhId": "1571601249",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1571601249",
"modified": "2023-10-09T11:41:57.472Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--a"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:37:38.983Z",
"description": "",
"namespace": "GN116",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-09T17:17:53.771Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-03-16T19:05:37.811Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-16T19:02:50.243Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:46:29.457Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-22T17:58:40.815Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:10:56.699Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:43:20.646Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:37:38.983Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"116"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DCLRE1C Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN116",
"entType": "SequenceVariantInterpretation",
"ldhId": "1565017043",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1565017043",
"modified": "2023-10-09T11:37:39.488Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--E"
},
{
"entContent": {
"description": "",
"namespace": "GN101",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:39:23.316Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:16:04.957Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:31.446Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"101"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTC1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN101",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535829270",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535829270",
"modified": "2024-03-25T21:16:05.057Z",
"modifier": "makelly2",
"rev": "_h6SHykO---"
},
{
"entContent": {
"description": "",
"namespace": "GN098",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T02:36:26.682Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:05.858Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:02.875Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"098"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNI3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN098",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535821566",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535821566",
"modified": "2024-03-25T21:15:06.031Z",
"modifier": "makelly2",
"rev": "_h6SHykK--P"
},
{
"entContent": {
"description": "VWD type 2N rule specifications",
"namespace": "GN090",
"releaseNotes": "",
"shortTitle": "von Willebrand Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-13T21:04:07.328Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2022-12-13T13:31:56.852Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-09T20:56:32.630Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-06T15:51:23.401Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-29T16:02:53.417Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-15T19:23:59.886Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T23:04:00.855Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"090"
],
"title": "ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN090",
"entType": "SequenceVariantInterpretation",
"ldhId": "1529372862",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529372862",
"modified": "2024-02-29T16:02:53.580Z",
"modifier": "leekristy",
"rev": "_h6SHykK--H"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome associated with the GP9 gene.",
"namespace": "GN083",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:28:28.440Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:01:50.473Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:42.735Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:40:46.282Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"083"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP9 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN083",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528072643",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528072643",
"modified": "2023-05-10T20:40:46.538Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyjy--E"
},
{
"entContent": {
"description": "",
"namespace": "GN075",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T15:02:00.319Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:36:34.270Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:37:05.831Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"075"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2D Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN075",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243145",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243145",
"modified": "2023-04-11T17:37:06.024Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--B"
},
{
"entContent": {
"approvedOn": "2023-10-05T13:24:37.478Z",
"description": "Hemophilia A",
"namespace": "GN071",
"releaseNotes": "Edits post SVI Review",
"shortTitle": "Coagulation Factor Deficiency Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T16:51:25.460Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-13T15:29:59.241Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-07T15:35:18.557Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-08T23:19:29.612Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-01T16:18:36.974Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-05T13:24:37.478Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"071"
],
"title": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN071",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243141",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243141",
"modified": "2023-10-05T13:24:38.065Z",
"modifier": "leekristy",
"rev": "_h6SHykS--R"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:43:29.634Z",
"description": "SCN8A",
"namespace": "GN070",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T16:02:50.886Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:59:43.168Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:32.036Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:32:41.896Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:05:22.669Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:47.538Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:28.189Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:43:29.634Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"070"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN070",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243140",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243140",
"modified": "2024-03-19T18:43:30.042Z",
"modifier": "laceysmith",
"rev": "_h6SHykG--i"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN065",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:29.942Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"065"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO15A Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN065",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243135",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243135",
"modified": "2022-08-18T19:14:33.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN056",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:52.441Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"056"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC26A4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN056",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243126",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243126",
"modified": "2022-08-18T19:13:56.516Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN055",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:48.554Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"055"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO7A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN055",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243125",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243125",
"modified": "2022-08-18T19:13:52.009Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--C"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN053",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:40.836Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"053"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN053",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243123",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243123",
"modified": "2022-08-18T19:13:44.249Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--A"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN046",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:12.804Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:27:14.680Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:25:24.102Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:35.383Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"046"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN046",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243116",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243116",
"modified": "2023-09-06T21:12:35.517Z",
"modifier": "sharriso",
"rev": "_h6SHykS--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN043",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:01.042Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:41:50.919Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:39:57.331Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:09.143Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"043"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN043",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243113",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243113",
"modified": "2023-09-06T21:12:09.271Z",
"modifier": "sharriso",
"rev": "_h6SHykG--E"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN040",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:49.407Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:33:42.890Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:31:56.497Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:39.602Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"040"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN040",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243110",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243110",
"modified": "2023-09-06T21:11:39.749Z",
"modifier": "sharriso",
"rev": "_h6SHykS--G"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:22:58.500Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN032",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:17.106Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:24:55.246Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:16:57.373Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:28.132Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:22:58.500Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"032"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN032",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243102",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243102",
"modified": "2023-09-29T15:16:49.280Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--V"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN031",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:11.889Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"031"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PDHA1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN031",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243101",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243101",
"modified": "2022-08-18T19:12:15.742Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6---"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:50:05.277Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for GATM (arginine:glycine amidinotransferase) Summary of ACMG-AMP Criteria for GATM Variants",
"namespace": "GN025",
"releaseNotes": "* Added supporting strength for PM3 and PM4. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:50:05.277Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T16:59:34.069Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2022-09-07T17:54:55.689Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:54:02.758Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:22.515Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"025"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN025",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243095",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243095",
"modified": "2023-10-11T16:59:34.312Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykC--N"
},
{
"entContent": {
"approvedOn": "2026-04-24T10:56:23.076Z",
"description": "ACADVL Specifications version 1.1 Test\n ",
"namespace": "GN021",
"releaseNotes": "* Test\n* Test 1\n* Demo ECT",
"shortTitle": "ACADVL Variant Curation Expert Panel",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "devScorer",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2026-04-24T10:56:23.076Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "neethus",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-09-10T21:33:01.424Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "devScorer",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2026-02-09T16:41:27.012Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T15:42:57.114Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "devScorer",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-02-09T16:39:55.100Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecSviApproverTest",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-04-24T10:56:09.093Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"021"
],
"title": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACADVL Version 1.2.0",
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015",
"version": "1.2.0",
"versioned": true
},
"entId": "GN021",
"entType": "SequenceVariantInterpretation",
"ldhId": "639509375",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639509375",
"modified": "2026-04-24T10:56:23.582Z",
"modifier": "devScorer",
"rev": "_lZ6gLjK---"
},
{
"entContent": {
"approvedOn": "2023-08-11T16:07:10.417Z",
"description": "This version specified for the following genes: HNF1A",
"namespace": "GN017",
"releaseNotes": "Corrections to combining rules \n\nAdding previously omitted PVS1 Decision Tree and PS2 Points Table\n\nIndicated that gnomAD v.3.1.2 should be used for PM1\\_Supporting/BA1/BS1 frequency criteria for variants not covered in v2.1.1 exomes (consistent with recommendations of gnomAD based on sample sizes)",
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-08-11T16:07:10.417Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-02-05T03:53:36.999Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-25T19:15:04.115Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-11T15:50:52.587Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-25T18:50:17.656Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"017"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0",
"version": "2.1.0",
"versioned": true
},
"entId": "GN017",
"entType": "SequenceVariantInterpretation",
"ldhId": "467903868",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467903868",
"modified": "2023-09-29T15:16:48.007Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--J"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"description": "This version specified for the following genes: ITGA2B, ITGB3",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN011",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"011"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1",
"version": "2.1.0"
},
"entId": "GN011",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637583",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637583",
"modified": "2023-09-29T15:16:47.242Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--I"
},
{
"entContent": {
"approvedOn": "2018-03-02T00:00:00.000Z",
"description": "ACMG variant classification (PAH)",
"namespace": "GN006",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/30311390"
}
],
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "ACMG variant classification (PAH)",
"specificationSource": "https://clinicalgenome.org/docs/clingen-pah-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2018-03-02T00:00:00.000Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-06T18:23:11.454Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-12-05T12:39:42.103Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": true,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-10T17:37:39.725Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"006"
],
"title": "ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0",
"versioned": true
},
"entId": "GN006",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637578",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637578",
"modified": "2024-03-10T17:37:40.064Z",
"modifier": "sharriso",
"rev": "_h6SHyk---O"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "2024-03-14T15:55:27.954Z",
"description": "ACMG Classification Rules Specified for PTEN Variant Curation",
"namespace": "GN003",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/30311380"
}
],
"releaseNotes": "Minor Changes: \n1\\. Correct SpliceAI cutoff for BP4 rule \n2\\. Correct the Rules for Combining Criteria \n3\\. Add BLOSUM matrix, Cleveland Clinic core and Pediatric score tables",
"releasedUnderRevision": true,
"shortTitle": "ACMG-PTEN Variant Curation Guideline",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "shengany",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-14T15:55:27.954Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "shengany",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-04T20:35:28.682Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "shengany",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-04T21:12:32.177Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-23T20:17:15.118Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "proberts",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-14T13:32:01.006Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"003"
],
"title": "ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0",
"version": "3.1.0",
"versioned": true
},
"entId": "GN003",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637575",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637575",
"modified": "2024-03-14T15:55:28.429Z",
"modifier": "shengany",
"rev": "_h6SHykW--M"
},
{
"created": "2026-02-09T19:53:59.126Z",
"creator": "devScorer",
"entContent": {
"namespace": "GN178",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "devScorer",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2026-02-09T19:53:50.641Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"178"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DAAM1 Version 1.0.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.0.0",
"versioned": true
},
"entId": "GN178",
"entType": "SequenceVariantInterpretation",
"ldhId": "2898618367",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/2898618367",
"modified": "2026-02-09T19:53:59.126Z",
"modifier": "devScorer",
"rev": "_lCN1xGm---"
},
{
"created": "2026-02-09T17:02:42.780Z",
"creator": "cspecVcepCoordinatorTest",
"entContent": {
"namespace": "GN177",
"releaseNotes": "",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2026-02-09T17:02:33.366Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"177"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.0.0",
"versioned": true
},
"entId": "GN177",
"entType": "SequenceVariantInterpretation",
"ldhId": "2898613358",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/2898613358",
"modified": "2026-02-09T17:02:42.780Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_lCLY9oG---"
},
{
"created": "2025-09-10T20:29:57.091Z",
"creator": "neethus",
"entContent": {
"description": "",
"namespace": "GN175",
"releaseNotes": "",
"shortTitle": "ACADVL Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2025-09-10T20:29:50.162Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2026-03-12T16:57:14.577Z"
},
"name": "Pilot Rules Submitted"
}
],
"tagNameSpaces": [
"175"
],
"title": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F10 Version 1.0.0",
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015",
"version": "1.0.0",
"versioned": true
},
"entId": "GN175",
"entType": "SequenceVariantInterpretation",
"ldhId": "2584058767",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/2584058767",
"modified": "2026-03-12T16:57:14.957Z",
"modifier": "neethus",
"rev": "_lMJ5Gd---_"
},
{
"created": "2024-03-15T12:25:56.710Z",
"creator": "coraleas",
"entContent": {
"description": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0",
"namespace": "GN173",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-03-15T12:25:53.310Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2026-01-21T21:07:29.360Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-04-30T07:48:35.395Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-08-05T17:14:28.070Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-08-29T14:07:17.275Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Approved For Release",
"timeStamp": "2026-01-21T20:43:03.354Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"173"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN173",
"entType": "SequenceVariantInterpretation",
"ldhId": "1745680620",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1745680620",
"modified": "2026-01-21T21:07:29.682Z",
"modifier": "devScorer",
"rev": "_k8HgPRK---"
},
{
"created": "2023-12-19T19:18:04.435Z",
"creator": "monicacsulit",
"entContent": {
"description": "DDC Specification Version 1.0",
"namespace": "GN163",
"releaseNotes": "",
"shortTitle": "Dopa Decarboxylase (Aromatic L-Amino Acid Decarboxylase) Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-12-19T19:18:00.403Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-03-14T22:05:05.195Z"
},
"name": "Classification Rules Submitted"
}
],
"tagNameSpaces": [
"163"
],
"title": "ClinGen Dopa Decarboxylase (Aromatic L-Amino Acid Decarboxylase) Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DDC Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN163",
"entType": "SequenceVariantInterpretation",
"ldhId": "1670130990",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1670130990",
"modified": "2024-03-14T22:05:05.376Z",
"modifier": "monicacsulit",
"rev": "_h6SHykG--J"
},
{
"created": "2023-11-02T19:33:25.416Z",
"creator": "schmidtj1",
"entContent": {
"namespace": "GN157",
"releaseNotes": "",
"shortTitle": "Leukodystrophy and Leukoencephalopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "schmidtj1",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-11-02T19:33:21.194Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"157"
],
"title": "ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN157",
"entType": "SequenceVariantInterpretation",
"ldhId": "1623526670",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1623526670",
"modified": "2023-11-02T19:33:25.416Z",
"modifier": "schmidtj1",
"rev": "_h6SHykG--A"
},
{
"created": "2023-10-16T13:25:03.384Z",
"creator": "coraleas",
"entContent": {
"description": "This version is specified for the following gene: HA2",
"namespace": "GN154",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-10-16T13:24:59.746Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"154"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN154",
"entType": "SequenceVariantInterpretation",
"ldhId": "1621633617",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1621633617",
"modified": "2023-10-16T13:25:03.384Z",
"modifier": "coraleas",
"rev": "_h6SHykK--F"
},
{
"created": "2023-09-04T12:30:11.735Z",
"creator": "mweaver",
"entContent": {
"description": "CPS1 specifications; created in tandem with the NAGS specifications.",
"namespace": "GN152",
"releaseNotes": "",
"shortTitle": "Urea Cycle Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-09-04T12:30:08.337Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-03-04T13:03:42.033Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-15T11:58:50.632Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-02-26T13:54:26.240Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"152"
],
"title": "ClinGen Urea Cycle Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CPS1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN152",
"entType": "SequenceVariantInterpretation",
"ldhId": "1616836621",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1616836621",
"modified": "2024-03-04T13:03:42.237Z",
"modifier": "mweaver",
"rev": "_h6SHyk---M"
},
{
"entContent": {
"description": "The Congenital Myopathies VCEP aims to (1) define criteria for the specific classification of variants related to congenital myopathies based on the ACMG standards and guidelines for variant interpretation and classification, and (2) review the majority of reported variants that have been associated with these disorders to provide expert-approved classification for their clinical significance, starting with 5 genes that have been described as having Definitive evidence for a causal role in disease: ACTA1, NEB, MTM1, DNM2, RYR1. ",
"namespace": "GN146",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-08-04T14:03:29.094Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-26T03:38:37.497Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-03T23:33:47.934Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"146"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NEB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN146",
"entType": "SequenceVariantInterpretation",
"ldhId": "1613756497",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1613756497",
"modified": "2024-02-26T03:38:37.775Z",
"modifier": "mtdistefano",
"rev": "_h6SHykG--e"
},
{
"entContent": {
"description": "Combined NAGS/CPS1 specifications",
"namespace": "GN143",
"releaseNotes": "",
"shortTitle": "Urea Cycle Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-19T14:45:07.683Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-03-04T12:40:44.680Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-15T11:52:26.807Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-02-26T15:03:05.229Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"143"
],
"title": "ClinGen Urea Cycle Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NAGS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN143",
"entType": "SequenceVariantInterpretation",
"ldhId": "1612106813",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1612106813",
"modified": "2024-03-04T12:40:44.865Z",
"modifier": "mweaver",
"rev": "_h6SHykK--I"
},
{
"entContent": {
"description": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 1.0.0",
"namespace": "GN139",
"releaseNotes": "",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-30T06:20:27.832Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-08T06:00:43.728Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-18T05:51:30.928Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-12T22:25:03.517Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"139"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN139",
"entType": "SequenceVariantInterpretation",
"ldhId": "1578297058",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1578297058",
"modified": "2024-03-08T06:00:43.895Z",
"modifier": "johnplaz",
"rev": "_h6SHykK--M"
},
{
"entContent": {
"namespace": "GN131",
"releaseNotes": "",
"shortTitle": "Kidney Cystic and Ciliopathy Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "proberts",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-05-10T14:33:01.757Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"131"
],
"title": "ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN131",
"entType": "SequenceVariantInterpretation",
"ldhId": "1572290283",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1572290283",
"modified": "2023-05-10T14:33:05.274Z",
"modifier": "proberts",
"rev": "_h6SHyj6--K"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:40:43.166Z",
"description": "",
"namespace": "GN123",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-27T20:57:21.333Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:50:45.180Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:14:22.402Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:44:53.614Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:40:43.166Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"123"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN123",
"entType": "SequenceVariantInterpretation",
"ldhId": "1567643911",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567643911",
"modified": "2023-10-09T11:40:43.625Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---F"
},
{
"entContent": {
"description": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0",
"namespace": "GN111",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-02-08T12:26:28.962Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"111"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN111",
"entType": "SequenceVariantInterpretation",
"ldhId": "1561019304",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1561019304",
"modified": "2023-02-08T12:26:33.453Z",
"modifier": "coraleas",
"rev": "_h6SHyj6--H"
},
{
"entContent": {
"description": "",
"namespace": "GN107",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-01-09T15:31:16.976Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:37:22.563Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:34:59.767Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"107"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN107",
"entType": "SequenceVariantInterpretation",
"ldhId": "1553377025",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1553377025",
"modified": "2023-04-11T17:35:00.089Z",
"modifier": "sharriso",
"rev": "_h6SHyjy---"
},
{
"entContent": {
"description": "",
"namespace": "GN104",
"releaseNotes": "",
"shortTitle": "Glaucoma Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-09T07:25:30.182Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-02-19T02:55:23.745Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-30T22:15:01.811Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-02-18T04:08:59.540Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"104"
],
"title": "ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CYP1B1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN104",
"entType": "SequenceVariantInterpretation",
"ldhId": "1536422161",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1536422161",
"modified": "2024-02-19T02:55:24.029Z",
"modifier": "esouzeau",
"rev": "_h6SHykW--E"
},
{
"entContent": {
"description": "",
"namespace": "GN100",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:24:58.208Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:41.902Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:22.430Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"100"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TPM1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN100",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535827397",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535827397",
"modified": "2024-03-25T21:15:42.007Z",
"modifier": "makelly2",
"rev": "_h6SHykK--Q"
},
{
"entContent": {
"description": "",
"namespace": "GN099",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:19:18.304Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:23.858Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:12.768Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"099"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNT2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN099",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535826188",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535826188",
"modified": "2024-03-25T21:15:24.008Z",
"modifier": "makelly2",
"rev": "_h6SHykG--N"
},
{
"entContent": {
"approvedOn": "2023-12-21T20:16:32.552Z",
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA1 and BRCA2",
"namespace": "GN092",
"releaseNotes": "Updates in v1.1: \nUpdated web-link for suggested co-segregation analysis tool (COOL) \nUpdated assigned PVS1 codes for some variants in Specifications Table 4 \nUpdated assigned PS3/BS3 codes for some variants in Specifications Table 9, including results updates from interim Findlay report \nCorrected typos and errors \nAdded Supplementary table 16 - mRNA assay evidence used to highlight IVS1/2 variants eligible for PVS1 (RNA) code \nClarified code combinations table in Specifications document: any conflicting pathogenic and benign evidence codes should be resolved using approach 2 (points system)",
"releasedUnderRevision": true,
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "mandyS",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-21T03:29:02.227Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-23T06:06:30.683Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-10T20:52:53.136Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T17:33:36.969Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-12-21T20:16:32.552Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-23T05:45:36.743Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"092"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN092",
"entType": "SequenceVariantInterpretation",
"ldhId": "1530970787",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1530970787",
"modified": "2023-12-21T20:16:33.144Z",
"modifier": "michaelP",
"rev": "_h6SHykW--_"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome associated with the GP1BB gene.",
"namespace": "GN082",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:24:29.972Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:03:09.005Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:54.589Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:39:45.728Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"082"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN082",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528071527",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528071527",
"modified": "2023-05-10T20:39:45.928Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyjy--D"
},
{
"entContent": {
"approvedOn": "2023-11-28T19:22:51.081Z",
"description": "Summary of ACMG-AMP Criteria for PALB2 associated with hereditary breast and pancreatic cancer",
"namespace": "GN077",
"releaseNotes": "Version 1.1 updates \nUpdated PS1 table to match Splicing SVI recommendations (PMID: 37352859) \nCorrected errors in verbiage/typos for BP4 \nChanged BP4 from not applicable to applicable to make application of BP4 for splicing more visible in CSPEC \nVerbiage update: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing \\[updated from error in typing that said shows impact\\] \nVerbiage update: \\*NOTE: BP4 splice predictions may not be used in conjunction with BP7\\_variable (RNA) \\[updated from just BP7 for clarification\\]. \nAdded BP4 under the combinations for Benign and LB classification \\[this was omitted in error\\]",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-19T19:40:21.917Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-17T16:41:21.334Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-01-04T19:06:13.746Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-20T16:56:25.278Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-28T19:18:26.994Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-28T19:22:51.081Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-17T16:21:04.033Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"077"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN077",
"entType": "SequenceVariantInterpretation",
"ldhId": "1526222356",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1526222356",
"modified": "2023-11-28T19:22:51.591Z",
"modifier": "meganholdren",
"rev": "_h6SHykW---"
},
{
"entContent": {
"description": "",
"namespace": "GN073",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T13:45:57.209Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:34:49.731Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:36:09.282Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"073"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN073",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243143",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243143",
"modified": "2023-04-11T17:36:09.541Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--_"
},
{
"entContent": {
"approvedOn": "2022-08-25T22:49:46.752Z",
"description": "",
"namespace": "GN072",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-07T19:39:10.992Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:32:59.443Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:34:41.999Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"072"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN072",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243142",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243142",
"modified": "2023-04-11T17:34:42.193Z",
"modifier": "sharriso",
"rev": "_h6SHykC--D"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN062",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:18.044Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"062"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTOR Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN062",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243132",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243132",
"modified": "2022-11-11T18:08:12.113Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--E"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN058",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:00.973Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"058"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for USH2A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN058",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243128",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243128",
"modified": "2022-08-18T19:14:04.611Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN057",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:56.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"057"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TECTA Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN057",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243127",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243127",
"modified": "2022-08-18T19:14:00.553Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN051",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:32.682Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"051"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for COCH Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN051",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243121",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243121",
"modified": "2022-08-18T19:13:36.425Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--_"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN048",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:20.429Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:50:54.076Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:49:40.294Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:53.839Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"048"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN048",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243118",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243118",
"modified": "2023-09-06T21:12:53.963Z",
"modifier": "sharriso",
"rev": "_h6SHykG--T"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN047",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:16.731Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:29:35.249Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:27:46.530Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:43.388Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"047"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN047",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243117",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243117",
"modified": "2023-09-06T21:12:43.520Z",
"modifier": "sharriso",
"rev": "_h6SHykS--J"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN042",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:57.208Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:38:42.348Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:37:09.802Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:00.498Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"042"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN042",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243112",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243112",
"modified": "2023-09-06T21:12:00.626Z",
"modifier": "sharriso",
"rev": "_h6SHykG--S"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN039",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:45.478Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:16:28.104Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:15:00.296Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:27.125Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"039"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN039",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243109",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243109",
"modified": "2023-09-06T21:11:27.252Z",
"modifier": "sharriso",
"rev": "_h6SHykG--D"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:23:41.958Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN033",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:21.126Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:04.208Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:35.379Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:44.472Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:23:41.958Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"033"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN033",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243103",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243103",
"modified": "2023-09-29T15:16:49.367Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---E"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN030",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:07.840Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"030"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC19A3 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN030",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243100",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243100",
"modified": "2022-08-18T19:12:11.423Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN023",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"023"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1",
"version": "1.0.0"
},
"entId": "GN023",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243093",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243093",
"modified": "2023-09-29T15:16:48.775Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--A"
},
{
"entContent": {
"approvedOn": "2022-01-05T00:00:00.000Z",
"description": "This version specified for the following genes: FBN1",
"namespace": "GN022",
"shortTitle": "FBN1 Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-01-05T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"022"
],
"title": "ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN022",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243092",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243092",
"modified": "2023-09-29T15:16:48.670Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--O"
},
{
"entContent": {
"approvedOn": "2023-11-28T19:21:26.653Z",
"description": "ACMG-modified rules specifications for ATM (autosomal dominant and autosomal recessive disorders)",
"namespace": "GN020",
"releaseNotes": "Release notes v1.2 \n• Updated verbiage from PVS1\\_O\\_Strength and BP7\\_O\\_Strength - Update: PVS1\\_Strength(RNA) and BP7\\_Strength(RNA) \n• Updated verbiage to clarify: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). \n• Update verbiage to clarify : Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2\\_supporting would not apply \n• Add same verbiage as PALB2 rules: Apply to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1\\_VS\\[RNA\\] is applied based on high quality observed splicing impact and must be NMD prone \n• Update typo: Update to: Do not use: ATM does not have a defined low rate of missense benign variation \n• Clarify in silico predictor verbiage (PP3/BP4 RNA details) \n• Update 1 VS + 1 supporting (not just PM2\\_supporting) reaches likely pathogenic \n• Updated PS1 tables to splicing group SVI tables \n• Added the supplementary tables from original rules that did not transfer into the CSPEC editor.",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP)",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-28T19:21:26.653Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-02-21T21:54:17.271Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-04T19:42:40.170Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-18T17:20:00.954Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-28T19:17:31.236Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-04T19:34:25.031Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"020"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.2.0",
"version": "1.2.0",
"versioned": true
},
"entId": "GN020",
"entType": "SequenceVariantInterpretation",
"ldhId": "639508985",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639508985",
"modified": "2024-03-04T19:42:40.436Z",
"modifier": "meganholdren",
"rev": "_h6SHykG--f"
},
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
},
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "2017-06-25T00:00:00.000Z",
"description": "Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel",
"namespace": "GN002",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29300372"
}
],
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "MYH7-associated inherited cardiomyopathies - adapted from ACMG/AMP",
"specificationSource": "https://clinicalgenome.org/docs/clingen-cardiomyopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-06-25T00:00:00.000Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2022-12-02T21:18:52.580Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:14:13.513Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:43:53.213Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-09-04T17:37:33.893Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"002"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0",
"versioned": true
},
"entId": "GN002",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637574",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637574",
"modified": "2025-09-04T17:37:34.296Z",
"modifier": "cspecAdministrator",
"rev": "_kPVMGDy--A"
},
{
"created": "2024-03-14T14:41:32.999Z",
"creator": "coraleas",
"entContent": {
"description": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0",
"namespace": "GN170",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-03-14T14:41:29.375Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"170"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN170",
"entType": "SequenceVariantInterpretation",
"ldhId": "1745574676",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1745574676",
"modified": "2024-03-14T14:41:32.999Z",
"modifier": "coraleas",
"rev": "_h6SHykG--I"
},
{
"created": "2024-02-26T04:23:08.462Z",
"creator": "mtdistefano",
"entContent": {
"description": "",
"namespace": "GN169",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-02-26T04:23:04.824Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-01T17:08:18.600Z"
},
"name": "Pilot Rules Submitted"
}
],
"tagNameSpaces": [
"169"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN169",
"entType": "SequenceVariantInterpretation",
"ldhId": "1743586723",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1743586723",
"modified": "2024-03-01T17:08:18.822Z",
"modifier": "mtdistefano",
"rev": "_h6SHyk---L"
},
{
"created": "2024-02-06T19:06:30.805Z",
"creator": "sadlersull",
"entContent": {
"namespace": "GN167",
"releaseNotes": "",
"shortTitle": "Leber Congenital Amaurosis/early onset Retinal Dystrophy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "sadlersull",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-02-06T19:06:26.385Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"167"
],
"title": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GUCY2D Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN167",
"entType": "SequenceVariantInterpretation",
"ldhId": "1733815116",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1733815116",
"modified": "2024-02-06T19:06:30.805Z",
"modifier": "sadlersull",
"rev": "_h6SHykW--C"
},
{
"created": "2024-01-12T19:53:00.859Z",
"creator": "kworley",
"entContent": {
"description": "CHM",
"namespace": "GN165",
"releaseNotes": "",
"shortTitle": "X-linked Inherited Retinal Disease Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "kworley",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-01-12T19:52:55.965Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"165"
],
"title": "ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CHM Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN165",
"entType": "SequenceVariantInterpretation",
"ldhId": "1670130992",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1670130992",
"modified": "2024-01-12T19:53:00.859Z",
"modifier": "kworley",
"rev": "_h6SHyk---I"
},
{
"created": "2023-09-13T17:01:34.347Z",
"creator": "abyrne",
"entContent": {
"namespace": "GN153",
"releaseNotes": "",
"shortTitle": "Kidney Cystic and Ciliopathy Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "abyrne",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-09-13T17:01:30.888Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"153"
],
"title": "ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN153",
"entType": "SequenceVariantInterpretation",
"ldhId": "1617736159",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1617736159",
"modified": "2023-09-13T17:01:34.347Z",
"modifier": "abyrne",
"rev": "_h6SHykC--G"
},
{
"entContent": {
"description": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 1.0.0",
"namespace": "GN138",
"releaseNotes": "",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-30T06:01:42.224Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-08T06:00:00.696Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-18T05:48:56.323Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-12T22:24:27.214Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"138"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN138",
"entType": "SequenceVariantInterpretation",
"ldhId": "1578294885",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1578294885",
"modified": "2024-03-08T06:00:00.814Z",
"modifier": "johnplaz",
"rev": "_h6SHykK--L"
},
{
"entContent": {
"approvedOn": "2024-03-20T16:14:11.019Z",
"description": "This version includes: \n-additional clarifying notes for not applying certain evidence codes together\n-updated HHT Phenotype attached document\n \n ",
"namespace": "GN136",
"releaseNotes": "This version includes: \n\\-additional clarifying notes for not applying certain evidence codes together \n\\-updated HHT Phenotype attached document",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Hemorrhagic Telangiectasia Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-15T18:11:03.293Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-18T14:05:03.065Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-31T14:44:45.584Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-20T16:10:54.460Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-20T16:14:11.019Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-14T14:13:24.650Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"136"
],
"title": "ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN136",
"entType": "SequenceVariantInterpretation",
"ldhId": "1576926543",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1576926543",
"modified": "2024-03-20T16:14:11.400Z",
"modifier": "ClinGenHHT1",
"rev": "_h6SHyk---Q"
},
{
"entContent": {
"approvedOn": "2024-03-20T16:13:39.132Z",
"description": "This version includes: \n-updated BMP10 interaction cluster residues (PM1)\n-additional clarifying notes for not applying certain evidence codes together\n-updated HHT Phenotype attached document\n \n ",
"namespace": "GN135",
"releaseNotes": "This version includes: \n\\-updated BMP10 interaction cluster residues (PM1) \n\\-additional clarifying notes for not applying certain evidence codes together \n\\-updated HHT Phenotype attached document",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Hemorrhagic Telangiectasia Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-06T13:23:21.464Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-18T14:04:39.580Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-31T14:44:55.292Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-20T16:10:44.487Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-20T16:13:39.132Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "ClinGenHHT1",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-14T13:24:59.727Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"135"
],
"title": "ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN135",
"entType": "SequenceVariantInterpretation",
"ldhId": "1576018567",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1576018567",
"modified": "2024-03-20T16:13:39.583Z",
"modifier": "ClinGenHHT1",
"rev": "_h6SHykW--Q"
},
{
"entContent": {
"description": "These are the ACMG/AMP variant classification specifications developed by the RASopathy VCEP.",
"namespace": "GN127",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-05-03T20:27:55.869Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T14:36:26.846Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-08T14:34:30.564Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:14:01.022Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"127"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN127",
"entType": "SequenceVariantInterpretation",
"ldhId": "1571593861",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1571593861",
"modified": "2023-09-06T21:14:01.169Z",
"modifier": "sharriso",
"rev": "_h6SHykG--G"
},
{
"entContent": {
"description": "RS1 gene variant curation specification",
"namespace": "GN126",
"releaseNotes": "",
"shortTitle": "X-linked Inherited Retinal Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-04-24T19:45:48.082Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-02-01T20:03:56.370Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-03-11T18:21:02.320Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"126"
],
"title": "ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN126",
"entType": "SequenceVariantInterpretation",
"ldhId": "1570648177",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1570648177",
"modified": "2024-03-11T18:21:02.604Z",
"modifier": "tsneddon",
"rev": "_h6SHyk---P"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:40:07.621Z",
"description": "",
"namespace": "GN121",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-21T22:10:40.847Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-03-30T16:37:56.603Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-30T16:35:15.478Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:48:10.575Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:13:42.769Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:44:31.391Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:40:07.621Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"121"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN121",
"entType": "SequenceVariantInterpretation",
"ldhId": "1567011281",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1567011281",
"modified": "2023-10-09T11:40:08.140Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--Y"
},
{
"entContent": {
"approvedOn": "2023-10-24T07:58:03.767Z",
"description": "LCA/eoRD Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65",
"namespace": "GN120",
"releaseNotes": "",
"shortTitle": "Leber Congenital Amaurosis/early onset Retinal Dystrophy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "sadlersull",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-15T15:19:16.788Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sadlersull",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-09-11T15:38:03.850Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-01T16:08:12.730Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-21T16:18:50.610Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "sadlersull",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-24T07:58:03.767Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"120"
],
"title": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN120",
"entType": "SequenceVariantInterpretation",
"ldhId": "1566365955",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1566365955",
"modified": "2023-10-24T07:58:04.455Z",
"modifier": "sadlersull",
"rev": "_h6SHykG--b"
},
{
"entContent": {
"description": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MMR genes Version 1.0.0",
"namespace": "GN115",
"releaseNotes": "",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-09T02:55:44.000Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-08T05:59:21.109Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-18T05:30:16.164Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-05-20T16:17:29.735Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"115"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN115",
"entType": "SequenceVariantInterpretation",
"ldhId": "1564688410",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1564688410",
"modified": "2025-05-20T16:17:30.211Z",
"modifier": "cspecSviApproverTest",
"rev": "_js36Vk6---"
},
{
"entContent": {
"approvedOn": "2023-10-09T11:35:57.945Z",
"description": "",
"namespace": "GN114",
"releaseNotes": "Additional variants requested were added.",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-08T15:51:46.533Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-03-16T19:06:13.935Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-16T19:02:43.285Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-30T21:44:32.650Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "vanessajacovas",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-30T17:34:37.230Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-22T15:09:24.503Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-20T13:42:31.102Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-09T11:35:57.945Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"114"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN114",
"entType": "SequenceVariantInterpretation",
"ldhId": "1564418400",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1564418400",
"modified": "2023-10-09T11:35:58.572Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--D"
},
{
"entContent": {
"description": "First Draft of NF1 Variant Rules",
"namespace": "GN109",
"releaseNotes": "",
"shortTitle": "Neurofibromatosis and Schwannomatosis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-01-11T16:57:18.283Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-01T04:29:27.484Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-08T19:14:45.749Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-08-30T17:09:22.583Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"109"
],
"title": "ClinGen Neurofibromatosis and Schwannomatosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NF1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN109",
"entType": "SequenceVariantInterpretation",
"ldhId": "1553923915",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1553923915",
"modified": "2023-08-30T17:09:22.936Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--F"
},
{
"entContent": {
"description": "",
"namespace": "GN108",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-01-10T21:02:39.376Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:37:43.777Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:36:34.758Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2025-02-04T13:15:44.418Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"108"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN108",
"entType": "SequenceVariantInterpretation",
"ldhId": "1553706895",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1553706895",
"modified": "2025-02-04T14:49:13.127Z",
"modifier": "cspecAdministrator",
"rev": "_jLDtxqa---"
},
{
"entContent": {
"description": "",
"namespace": "GN103",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:51:57.215Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:16:58.725Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:45:07.830Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"103"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYL3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN103",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535831942",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535831942",
"modified": "2024-03-25T21:16:58.836Z",
"modifier": "makelly2",
"rev": "_h6SHyk---S"
},
{
"entContent": {
"description": "",
"namespace": "GN102",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:47:34.311Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:16:25.641Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:56.388Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"102"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYL2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN102",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535830806",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535830806",
"modified": "2024-03-25T21:16:25.786Z",
"modifier": "makelly2",
"rev": "_h6SHykO--_"
},
{
"entContent": {
"description": "",
"namespace": "GN091",
"releaseNotes": "",
"shortTitle": "Lysosomal Storage Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-17T15:07:17.321Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-19T12:29:38.431Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-31T16:50:23.475Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-28T20:02:05.227Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-12-14T22:51:01.515Z"
},
"name": "Pilot Rules Submitted"
}
],
"tagNameSpaces": [
"091"
],
"title": "ClinGen Lysosomal Storage Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN091",
"entType": "SequenceVariantInterpretation",
"ldhId": "1529725529",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529725529",
"modified": "2023-12-14T22:51:01.740Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykG--c"
},
{
"entContent": {
"description": "RMRP specifications",
"namespace": "GN088",
"releaseNotes": "",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-12T14:52:32.692Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-09-13T17:34:40.911Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-07-20T17:44:14.855Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-10-27T20:45:39.139Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"088"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RMRP Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN088",
"entType": "SequenceVariantInterpretation",
"ldhId": "1529230095",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529230095",
"modified": "2023-10-27T20:45:39.390Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHykG--_"
},
{
"entContent": {
"approvedOn": "2023-08-11T16:06:02.452Z",
"description": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version",
"namespace": "GN086",
"releaseNotes": "Indicated that gnomAD v.3.1.2 genomes should be used for variants not covered in v2.1.1 exomes for PM2\\_Supporting/BA1/BS1 based on sample size and consistent with gnomAD guidance\n\nInheritance pattern for GCK/monogenic diabetes has been updated to “Semidominant\" per what has already been recommended and approved by the SVI.",
"releasedUnderRevision": true,
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-03T19:46:15.093Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-05T21:31:26.044Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-11T15:50:34.569Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-08-11T16:06:02.452Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-12-03T02:45:17.691Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-09T15:59:06.054Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-09T17:46:51.251Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"086"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0",
"version": "1.3.0",
"versioned": true
},
"entId": "GN086",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528339111",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528339111",
"modified": "2024-03-05T21:31:26.464Z",
"modifier": "tonipollin",
"rev": "_h6SHykK--K"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome",
"namespace": "GN079",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:45:18.591Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:02:49.573Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:24.643Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:38:19.850Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"079"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN079",
"entType": "SequenceVariantInterpretation",
"ldhId": "1527857178",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527857178",
"modified": "2023-05-10T20:38:20.101Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyj6--L"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:41:33.170Z",
"description": "SCN2A",
"namespace": "GN068",
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-25T17:16:49.110Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:57:33.256Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:34:48.630Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:28.452Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:04:45.784Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:44.233Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:24.630Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:41:33.170Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-09-04T17:42:03.882Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"068"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN068",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243138",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243138",
"modified": "2025-09-04T17:42:04.295Z",
"modifier": "cspecAdministrator",
"rev": "_kPVQNv2---"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN063",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:21.885Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"063"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CA Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN063",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243133",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243133",
"modified": "2022-11-11T18:08:12.252Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--C"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN060",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:09.607Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"060"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGB3 Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN060",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243130",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243130",
"modified": "2022-08-18T19:14:13.243Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--B"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN050",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:28.663Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"050"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN050",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243120",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243120",
"modified": "2022-08-18T19:13:32.244Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--_"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN044",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:04.995Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:47:09.101Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:45:31.721Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:17.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"044"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN044",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243114",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243114",
"modified": "2023-09-06T21:12:18.143Z",
"modifier": "sharriso",
"rev": "_h6SHykS--H"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:03.587Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN036",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:33.027Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:31.618Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:18.754Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:03.587Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-05T20:41:20.182Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"036"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN036",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243106",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243106",
"modified": "2024-03-05T20:41:20.422Z",
"modifier": "arossel",
"rev": "_h6SHyk---N"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:47.151Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN035",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:29.035Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:49.658Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:49.295Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:06.342Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:47.151Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"035"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN035",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243105",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243105",
"modified": "2023-09-29T15:16:49.547Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--K"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:20.029Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN034",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:25.125Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:29:08.581Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:29.320Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:54.202Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:20.029Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-08-09T16:35:12.943Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"034"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN034",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243104",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243104",
"modified": "2024-08-09T16:35:13.387Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_iRd8f2K---"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN029",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:03.420Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"029"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ETHE1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN029",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243099",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243099",
"modified": "2022-08-18T19:12:07.364Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju---"
},
{
"entContent": {
"approvedOn": "2024-01-30T20:28:04.228Z",
"description": "1. BA1/BS1/PM2 Clarification: In light of the recent release of gnomAD v4.0.0 without a (non-cancer) filter, removed the (non-cancer) text and added the following clarifying instruction: \"In general, the most recent/most comprehensive gnomAD version should be used.\"\n2. Criteria Combination Clarification: Added a general comment to the C Spec asking users to disregard the \"Rules for Combining Criteria\" section and instead use the \"Evidence Criteria Combinations\" table.",
"namespace": "GN024",
"releaseNotes": "1\\. BA1/BS1/PM2 Clarification: In light of the recent release of gnomAD v4.0.0 without a (non-cancer) filter, removed the (non-cancer) text and added the following clarifying instruction: \"In general, the most recent/most comprehensive gnomAD version should be used.\" \n2\\. Criteria Combination Clarification: Added a general comment to the C Spec asking users to disregard the \"Rules for Combining Criteria\" section and instead use the \"Evidence Criteria Combinations\" table.",
"releasedUnderRevision": true,
"shortTitle": "DICER1 and miRNA-Processing Gene Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "dagherjn",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-01-30T20:28:04.228Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "dagherjn",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-01-12T14:05:36.850Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "dagherjn",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-12T14:22:54.865Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-30T17:13:33.713Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"024"
],
"title": "ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0",
"version": "1.3.0",
"versioned": true
},
"entId": "GN024",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243094",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243094",
"modified": "2024-01-30T20:28:04.789Z",
"modifier": "dagherjn",
"rev": "_h6SHykK--G"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "2026-04-23T19:45:20.033Z",
"description": "ClinGen PH Expert Panel Specifications to the ACMG/AMP Variant Interpretation\nGuidelines for BMPR2 Version 1.0.0",
"namespace": "GN125",
"releaseNotes": "formatting edit only",
"shortTitle": "Pulmonary Hypertension Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cbw13@columbia.edu",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-04-03T21:16:21.925Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2026-01-28T16:23:51.173Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "cbw13@columbia.edu",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-18T17:35:58.159Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-12-29T19:12:23.288Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecSviApproverTest",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-02-05T18:11:06.282Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"modifiedBy": "cbw13@columbia.edu",
"name": "pilot-rules-reviewed",
"prevState": "Approved For Release",
"timeStamp": "2024-01-11T14:19:44.628Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "neethus",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2026-04-23T19:45:20.033Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "cbw13@columbia.edu",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-06-04T19:24:30.007Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "pilot-rules-reviewed",
"prevState": "Approved For Release",
"timeStamp": "2026-01-28T20:43:03.354Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"125"
],
"title": "ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.2.0",
"type": "Richards et.al., 2015 - Combining rules",
"version": "1.2.0",
"versioned": true
},
"entId": "GN125",
"entType": "SequenceVariantInterpretation",
"ldhId": "1568416522",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1568416522",
"modified": "2026-04-23T19:45:20.521Z",
"modifier": "neethus",
"rev": "_lZteFoy---"
},
{
"entContent": {
"approvedOn": "2024-03-28T18:26:03.720Z",
"description": "TP53 Rule Specifications for the ACMG/AMP Variant Curation Guidelines",
"namespace": "GN009",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/33300245/"
}
],
"releaseNotes": "1. Major version 2 VCEP updates with SVI feedback from first submission incorporated\n2. Points based evidence combining criteria based on modified Bayesian points system\n3. V2 Pilot added for SVI review",
"releasedUnderRevision": true,
"shortTitle": "TP53 VCEP ACMG/AMP Specifications",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-28T18:26:03.720Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-08-08T17:58:02.852Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-18T14:13:49.380Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-28T18:25:50.965Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-07T19:00:30.101Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-16T19:42:02.220Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"009"
],
"title": "ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0",
"version": "2.0.0",
"versioned": true
},
"entId": "GN009",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637581",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637581",
"modified": "2024-08-08T17:58:03.250Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_iRKi-Oq---"
},
{
"created": "2024-03-15T11:52:05.133Z",
"creator": "coraleas",
"entContent": {
"description": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"namespace": "GN171",
"releaseNotes": "",
"shortTitle": "Hemoglobinopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "coraleas",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-03-15T11:52:01.216Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"171"
],
"title": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN171",
"entType": "SequenceVariantInterpretation",
"ldhId": "1745676386",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1745676386",
"modified": "2024-03-15T11:52:05.133Z",
"modifier": "coraleas",
"rev": "_h6SHykG--g"
},
{
"created": "2024-02-12T18:50:09.706Z",
"creator": "enadeau1",
"entContent": {
"description": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MUTYH Version 1.0.0",
"namespace": "GN168",
"releaseNotes": "",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2024-02-12T18:50:05.775Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-07-25T11:52:18.437Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-07-25T11:59:19.566Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-07-25T11:59:19.566Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2024-07-25T12:00:01.214Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"168"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MUTYH Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN168",
"entType": "SequenceVariantInterpretation",
"ldhId": "1742141534",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1742141534",
"modified": "2024-07-25T12:00:01.782Z",
"modifier": "cspecSviApproverTest",
"rev": "_iMlBKOa---"
},
{
"entContent": {
"description": "",
"namespace": "GN148",
"releaseNotes": "",
"shortTitle": "Congenital Myopathies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-08-28T19:47:10.498Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-26T03:53:03.540Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-03T23:34:15.963Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"148"
],
"title": "ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DNM2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN148",
"entType": "SequenceVariantInterpretation",
"ldhId": "1616103420",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1616103420",
"modified": "2024-02-26T03:53:03.759Z",
"modifier": "mtdistefano",
"rev": "_h6SHykW--G"
},
{
"entContent": {
"description": "",
"namespace": "GN145",
"releaseNotes": "",
"shortTitle": "Charcot-Marie-Tooth Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-27T15:42:26.345Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2024-02-16T20:47:02.716Z"
},
"name": "Classification Rules Submitted"
}
],
"tagNameSpaces": [
"145"
],
"title": "ClinGen Charcot-Marie-Tooth Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SORD Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN145",
"entType": "SequenceVariantInterpretation",
"ldhId": "1612931797",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1612931797",
"modified": "2024-02-16T20:47:02.957Z",
"modifier": "Klatchman",
"rev": "_h6SHyk---K"
},
{
"entContent": {
"description": "ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD2 Version 1.0.0",
"namespace": "GN142",
"releaseNotes": "",
"shortTitle": "Kidney Cystic and Ciliopathy Disorders Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "proberts",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-12T18:32:49.597Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"142"
],
"title": "ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PKD2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN142",
"entType": "SequenceVariantInterpretation",
"ldhId": "1611476290",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1611476290",
"modified": "2023-07-12T18:32:53.233Z",
"modifier": "proberts",
"rev": "_h6SHykC--E"
},
{
"entContent": {
"description": "This submission includes the revised PIK3CD specifications prior pilot phase.",
"namespace": "GN141",
"releaseNotes": "",
"shortTitle": "Antibody Deficiencies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-06T19:48:24.064Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-06T20:10:28.196Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-07-12T21:48:09.826Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"141"
],
"title": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CD Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN141",
"entType": "SequenceVariantInterpretation",
"ldhId": "1610842289",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1610842289",
"modified": "2023-07-12T21:48:10.276Z",
"modifier": "abyrne",
"rev": "_h6SHykC--F"
},
{
"entContent": {
"description": "These specifications were modified in the context of gain of function PIK3CD variants conferring Autoimmune Lymphoproliferative syndrome 1 (APDS-1).",
"namespace": "GN140",
"releaseNotes": "",
"shortTitle": "Antibody Deficiencies Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "alejandronietopatlan",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-07-06T17:38:55.076Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-17T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"140"
],
"title": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CD Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN140",
"entType": "SequenceVariantInterpretation",
"ldhId": "1610830615",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1610830615",
"modified": "2023-10-03T18:24:46.115Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--L"
},
{
"entContent": {
"namespace": "GN134",
"releaseNotes": "",
"shortTitle": "Motile Ciliopathy Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "marwa_elnagheeb",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-06-02T13:25:11.096Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"134"
],
"title": "ClinGen Motile Ciliopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DNAH5 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN134",
"entType": "SequenceVariantInterpretation",
"ldhId": "1575652650",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1575652650",
"modified": "2023-06-02T13:25:14.462Z",
"modifier": "marwa_elnagheeb",
"rev": "_h6SHykS--E"
},
{
"entContent": {
"description": "These are the ACMG/AMP variant classification specifications developed by the RASopathy VCEP for PPP1CB.",
"namespace": "GN128",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-05-03T20:33:25.446Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T14:38:02.257Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-08T14:36:54.827Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:14:19.220Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"128"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN128",
"entType": "SequenceVariantInterpretation",
"ldhId": "1571595292",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1571595292",
"modified": "2023-09-06T21:14:19.361Z",
"modifier": "sharriso",
"rev": "_h6SHykS--L"
},
{
"entContent": {
"description": "LGMD VCEP Specifications, version 1",
"namespace": "GN117",
"releaseNotes": "",
"shortTitle": "Limb Girdle Muscular Dystrophy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "macalalad",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-03-10T19:51:58.235Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-07-23T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"117"
],
"title": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN117",
"entType": "SequenceVariantInterpretation",
"ldhId": "1565662061",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1565662061",
"modified": "2024-07-23T11:23:11.572Z",
"modifier": "cspecAdministrator",
"rev": "_iL7St02---"
},
{
"entContent": {
"description": "RPGR specifications",
"namespace": "GN106",
"releaseNotes": "",
"shortTitle": "X-linked Inherited Retinal Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2023-01-04T17:34:59.020Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-04-24T19:26:50.116Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-24T19:25:14.323Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-08-28T02:01:08.674Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-23T00:18:30.881Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": true,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-24T14:03:37.952Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"106"
],
"title": "ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN106",
"entType": "SequenceVariantInterpretation",
"ldhId": "1552193476",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1552193476",
"modified": "2024-03-24T14:03:38.155Z",
"modifier": "kworley",
"rev": "_h6SHykK--O"
},
{
"entContent": {
"description": "ABCD1 specifications v 1.0",
"namespace": "GN105",
"releaseNotes": "",
"shortTitle": "Peroxisomal Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-13T16:34:55.815Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-20T12:45:20.953Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-16T15:49:57.888Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-02-03T20:00:51.205Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-01T11:41:19.524Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"105"
],
"title": "ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN105",
"entType": "SequenceVariantInterpretation",
"ldhId": "1537428517",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1537428517",
"modified": "2023-09-01T11:41:19.882Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyjy--G"
},
{
"entContent": {
"description": "",
"namespace": "GN095",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-30T01:28:32.222Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:14:44.416Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-18T15:45:30.029Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"095"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYBPC3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN095",
"entType": "SequenceVariantInterpretation",
"ldhId": "1535304680",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535304680",
"modified": "2024-03-25T21:14:44.521Z",
"modifier": "makelly2",
"rev": "_h6SHyk---R"
},
{
"entContent": {
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA2",
"namespace": "GN093",
"releaseNotes": "",
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "mandyS",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-21T03:40:39.955Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-01-17T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"093"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN093",
"entType": "SequenceVariantInterpretation",
"ldhId": "1530972301",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1530972301",
"modified": "2023-01-27T21:47:10.559Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--F"
},
{
"entContent": {
"approvedOn": "2023-11-24T13:46:56.766Z",
"description": "The following criteria are for classic or attenuated familial adenomatous polyposis only and does not apply to Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, MONDO:0017790).\nThe preferred transcript for coding, intronic and promoter 1A variants is NM_000038.6 (MANE transcript). The NM_001127510.2 transcript differs from NM_000038.6 in the number of \"non-coding\" exons in the 5' region, which results in different exon numbering (in NM_000038.6 there is only one non-coding exon, in NM_001127510.2 there is one additional non-coding exon and one non-coding exon overlapping with NM_000038.6; the 15 coding exons are the same). For the promoter 1B deletion the preferred transcript is NM_001127511.3, which has an alternative coding exon 1. The LRG_130 summarizes all three “additional” exons of the previously mentioned transcripts, resulting in 18 exons). To standardize, variants in this document are described in HGVS nomenclature according to their positions in the NM_000038.6 transcript unless otherwise specified. Numbered exons in this document refers to exons 1-16 in the NM_000038.6transcript. Refer to Supplementary Table 1 for exon number conversions. \nIt is important to note that these criteria are not developed for low/moderate penetrant variants (e. g. c.3920T>A p.(Ile1307Lys) and c.3949G>C p.(Glu1317Gln)).",
"namespace": "GN089",
"releaseNotes": "* Correction of some inaccuracies in the Rules for Combining Criteria.\n* Addition of some relevant instructions out of the supplementary material\n* Change in Fig. 1A: Update of the possible pathways for “G to non-G changes”\n* Change in Fig. 1B: Transfer of splice variants c.136-1G>A,C,T; c.136-2A>C,G,T; c.220+1G>A,C,T and c.220+2T>A,C,G from List E to List A and transfer of c.220G>A,C,T from List E to List B based on RNA and phenotype data\n* Update of the supplementary material file.",
"releasedUnderRevision": true,
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "xiaoyuyin",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-13T04:32:42.802Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-10-20T13:21:03.456Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-20T13:04:16.330Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-21T20:45:32.523Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "ispier",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-24T13:46:56.766Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-14T10:53:29.300Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-17T17:10:15.332Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-20T13:04:16.330Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"089"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0",
"version": "2.1.0",
"versioned": true
},
"entId": "GN089",
"entType": "SequenceVariantInterpretation",
"ldhId": "1529292791",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529292791",
"modified": "2023-11-24T13:46:57.319Z",
"modifier": "ispier",
"rev": "_h6SHykS--S"
},
{
"entContent": {
"description": "",
"namespace": "GN087",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-04T18:05:53.296Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T14:33:57.587Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-06T16:51:27.119Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-08T14:30:32.836Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:31.945Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"087"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN087",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528438490",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528438490",
"modified": "2023-09-06T21:13:32.160Z",
"modifier": "sharriso",
"rev": "_h6SHykG--U"
},
{
"entContent": {
"approvedOn": "2023-10-11T00:08:05.287Z",
"description": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines ",
"namespace": "GN085",
"releaseNotes": "Upgrade initiation codon variants from PVS1\\_Moderate to PVS1\\_Strong on the basis that next methionine is Met71 and multiple variants not found in gnomAD have been reported in patients meeting diagnostic criteria for MODY (PMID: 23348805)",
"releasedUnderRevision": true,
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-03T19:43:58.274Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-09-15T17:57:42.509Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-10T20:03:39.521Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-11T00:08:05.287Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-11T00:09:15.508Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-25T18:51:29.117Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"085"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0",
"version": "2.0.0",
"versioned": true
},
"entId": "GN085",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528338151",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528338151",
"modified": "2023-10-11T00:08:05.798Z",
"modifier": "tonipollin",
"rev": "_h6SHykC--M"
},
{
"entContent": {
"approvedOn": "2023-07-17T13:46:49.999Z",
"description": "Rule specifications for antithrombin deficiency.",
"namespace": "GN084",
"releaseNotes": "All requested edits were made in this document and in the VCI, with exception of one. We would like the p.Cys29= variant to remain a VUS since there is only one benign code assigned. The point counting system is currently only being applied when conflicting rules codes are applied.",
"shortTitle": "Thrombosis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:36:49.338Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-02-05T17:13:29.702Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-01-30T22:24:12.728Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-10T20:24:41.947Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-07-17T13:46:49.999Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"084"
],
"title": "ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN084",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528074022",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528074022",
"modified": "2023-09-29T15:16:49.944Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--Q"
},
{
"entContent": {
"description": "Rule specifications for von Willebrand disease type 2A, 2B and 2M.",
"namespace": "GN081",
"releaseNotes": "",
"shortTitle": "von Willebrand Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T17:46:24.625Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2022-12-13T13:32:24.226Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-09T20:57:53.636Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-06T15:51:24.825Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-29T16:03:23.651Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-15T19:22:14.559Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T22:59:24.376Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"081"
],
"title": "ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN081",
"entType": "SequenceVariantInterpretation",
"ldhId": "1528062415",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528062415",
"modified": "2024-02-29T16:03:23.854Z",
"modifier": "leekristy",
"rev": "_h6SHykG--H"
},
{
"entContent": {
"approvedOn": "2024-02-29T04:26:34.603Z",
"description": "",
"namespace": "GN078",
"releaseNotes": "Please see clarifications made to PM2, BA1 and BS1. We updated language to gnomAD v4, removed language around using the “non-cancer” set (which did not contain TCGA germline samples) as this set is no longer used in v4. We changed PM2\\_Supporting from complete absence in gnomAD to PM2\\_Supporting ≤ 1.56E-6 GroupMax FAF. This is one order of magnitude less than the BS1 cut-off and strictly limits the presence of variants in gnomAD v4 but does not require complete absence.",
"releasedUnderRevision": true,
"shortTitle": "VHL Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:36:26.972Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-07-12T12:47:31.707Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-23T14:19:44.628Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Approved For Release",
"timeStamp": "2024-01-09T14:19:44.628Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-29T17:07:02.255Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-02-29T04:26:34.603Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-07-12T12:46:39.238Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"078"
],
"title": "ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN078",
"entType": "SequenceVariantInterpretation",
"ldhId": "1527855755",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527855755",
"modified": "2024-07-12T12:47:31.963Z",
"modifier": "devScorer",
"rev": "_iIZ6-mm---"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:42:37.373Z",
"description": "SCN3A",
"namespace": "GN069",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T15:36:15.462Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:58:27.926Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:11.910Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:31.278Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:05:04.244Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:46.152Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:26.429Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:42:37.373Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"069"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN069",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243139",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243139",
"modified": "2024-03-19T18:42:37.860Z",
"modifier": "laceysmith",
"rev": "_h6SHykW--P"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN064",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:25.817Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"064"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R2 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN064",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243134",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243134",
"modified": "2022-11-11T18:08:12.421Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--B"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN059",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:05.385Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"059"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGA2B Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN059",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243129",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243129",
"modified": "2022-08-18T19:14:09.167Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--D"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN052",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:36.877Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"052"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GJB2 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN052",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243122",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243122",
"modified": "2022-08-18T19:13:40.396Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--A"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN028",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:11:58.490Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"028"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for POLG Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN028",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243098",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243098",
"modified": "2022-08-18T19:12:02.919Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--_"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:50:38.411Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for GAMT (guanidinoacetate methytransferase) Summary of ACMG-AMP Criteria for GAMT Variants",
"namespace": "GN026",
"releaseNotes": "* Added supporting strength for PM3 and PM4. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:50:38.411Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T18:00:36.255Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-13T19:23:33.152Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:55:19.342Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:12.780Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"026"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN026",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243096",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243096",
"modified": "2024-02-13T19:23:33.426Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykW--D"
},
{
"entContent": {
"approvedOn": "2021-09-15T00:00:00.000Z",
"description": "MM-VCEP ACMG/AMP specifications for RUNX1",
"namespace": "GN008",
"releaseNotes": "\n(1) New REVEL thresholds for PP3 ≥ 0.88 and for BP4 ≤ 0.50 (originally PP3 ≥ 0.75 and BP4 ≤ 0.15).\n(2) Use SpliceAI as the primary in-silico splicing predictor replacing MES and SSF. The thresholds for SpliceAI ≥ 0.38 for PP3 and ≤ 0.20 for BP4. \n(3) PP3 can be applied for missense, synonymous, intronic and non-coding variants if the variant impacts splicing, including the creation of cryptic novel splice sites.\n(4) New conservation threshold for phyloP100 way (GRCh38/hg38) ≤2.0 for BP7 (originally PhyloP score < 0.1).\n(5) New amino acid range for PM1_supporting and PM4_supporting to AA 89-204 (originally AA105-204).\n(6) Apply PM5_supporting to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).\n(7) PM2 is downgraded to PM2_supporting.\n(8) Use of the Bayesian point system in curations with conflicting evidence.\n(9) Remove the previous location requirements (+7/-21 in BP7 and ±3/±5 in PP3) for intronic variants in BP7 and PP3. And remove the usage for UTR variants in PP3/BP4/BP7.\n",
"shortTitle": "Myeloid Malignancy Specification",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50034/docs/assertion-criteria ",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-09-15T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"008"
],
"title": "ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0"
},
"entId": "GN008",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637580",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637580",
"modified": "2023-09-29T15:16:45.795Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--H"
},
{
"entContent": {
"approvedOn": "2024-10-30T12:32:26.289Z",
"description": "This version specified for the following genes: CDH1",
"namespace": "GN007",
"releaseNotes": "(1) Specification of PM5\\_Supporting to nonsense and frameshift variants that are predicted/proved to undergo nonsense-mediated decay (NMD) or located upstream of the last known pathogenic truncating variant \\[c.2506G>T (p.Glu836Ter)\\]. \n(2) Column correction for PM2\\_Supporting from Moderate column to Supporting column.",
"releasedUnderRevision": true,
"shortTitle": "CDH1 Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-10-30T12:32:26.289Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-04-03T19:03:16.703Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-10-30T12:31:13.028Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "cspecSviApproverTest",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-10-30T12:32:14.199Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"007"
],
"title": "ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH1 Version 3.2.0",
"version": "3.2.0",
"versioned": true
},
"entId": "GN007",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637579",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637579",
"modified": "2024-10-30T12:32:26.996Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzns3e---"
},
{
"entContent": {
"approvedOn": "2021-11-09T00:00:00.000Z",
"description": "This version is specified for the following genes: LDLR",
"namespace": "GN013",
"notes": "",
"references": [],
"releaseNotes": "Updated for clarification on PM3 and BP2, and typo correction.",
"shortTitle": "ACMG variant classification Familial Hypercholesterolemia",
"specificationSource": "https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-09T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"013"
],
"title": "ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2",
"version": "1.2.0"
},
"entId": "GN013",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637573",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637573",
"modified": "2023-09-29T15:16:47.524Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---B"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "ACMG",
"fullBaseName": "American College of Medical Genetics and Genomics",
"shortTitle": "ACMG",
"title": "American College of Medical Genetics and Genomics",
"type": "Expert Panel"
},
"entId": "ACMG",
"entIri": "https://www.acmg.net",
"entType": "Organization",
"ldhId": "647188063",
"ldhIri": "https://genboree.org/cspec/Organization/id/647188063",
"modified": "2022-05-10T00:20:54.288Z",
"modifier": "neethus",
"rev": "_h6SHyEq--O"
}
]
},
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-06-25T00:00:00.000Z",
"description": "Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel",
"namespace": "GN002",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29300372"
}
],
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "MYH7-associated inherited cardiomyopathies - adapted from ACMG/AMP",
"specificationSource": "https://clinicalgenome.org/docs/clingen-cardiomyopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-06-25T00:00:00.000Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2022-12-02T21:18:52.580Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:14:13.513Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:43:53.213Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2025-09-04T17:37:33.893Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"002"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0",
"versioned": true
},
"entId": "GN002",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "002_PP5_nuclear_MYH7",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYH7"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "002",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432780",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432780",
"modified": "2022-01-19T20:31:28.477Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--E"
},
{
"entContent": {
"_uniqueProp": "002_PP2_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "002",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637792",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637792",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--B"
},
{
"entContent": {
"_uniqueProp": "002_BP1_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "002",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637778",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637778",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--F"
},
{
"entContent": {
"_uniqueProp": "002_PM5_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "002",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "105",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change previously established as pathogenic",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637777",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637777",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--E"
},
{
"entContent": {
"_uniqueProp": "002_BS2_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "002",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0069",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637774",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637774",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--G"
},
{
"entContent": {
"_uniqueProp": "002_PM3_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "002",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637773",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637773",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--O"
},
{
"entContent": {
"_uniqueProp": "002_BP6_nuclear_MYH7",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYH7"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "002",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432779",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432779",
"modified": "2022-01-19T20:31:28.477Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--D"
},
{
"entContent": {
"_uniqueProp": "002_BP7_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "002",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "117",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A silent variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site -AND- the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637794",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637794",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--T"
},
{
"entContent": {
"_uniqueProp": "002_PP3_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "002",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "100",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637793",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637793",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--S"
},
{
"entContent": {
"_uniqueProp": "002_BA1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "002",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "102",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is >= 0.1% based on the filtering allele frequency (FAF) in ExAC",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637791",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637791",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--A"
},
{
"entContent": {
"_uniqueProp": "002_PS4_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "002",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "111",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls -OR- Variant identified in ≥15 probands with consistent phenotypes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "123",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant identified in >=6 probands with consistent phenotypes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "115",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant identified in >=2 probands with consistent phenotypes",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637788",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637788",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--J"
},
{
"entContent": {
"_uniqueProp": "002_PS3_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "002",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "109",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637785",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637785",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--H"
},
{
"entContent": {
"_uniqueProp": "002_PS2_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "De novo Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "002",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "112",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (paternity confirmed) in a patient with disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637783",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637783",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--R"
},
{
"entContent": {
"_uniqueProp": "002_PM4_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "002",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "108",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637775",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637775",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--_"
},
{
"entContent": {
"_uniqueProp": "002_PM2_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "002",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "104",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Absent/extremely rare (<0.004%) from large population studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637797",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637797",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--_"
},
{
"entContent": {
"_uniqueProp": "002_PM1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "002",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "107",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Hotspot/est. functional domain (amino acids 181-937) without benign variation",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637796",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637796",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--K"
},
{
"entContent": {
"_uniqueProp": "002_PP4_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Other Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "002",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637795",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637795",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--U"
},
{
"entContent": {
"_uniqueProp": "002_BP5_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Other Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "002",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "119",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637790",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637790",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--L"
},
{
"entContent": {
"_uniqueProp": "002_PM6_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "De novo Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "002",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "106",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637780",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637780",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--H"
},
{
"entContent": {
"_uniqueProp": "002_PVS1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "002",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "114",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null Variant in gene with evidence supporting LOF as disease mechanism",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637789",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637789",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--K"
},
{
"entContent": {
"_uniqueProp": "002_PP1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "002",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "103",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant segregates with >= 7 meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "113",
"instructionsToUse": "",
"specificationType": [
"Modified rule strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant segragates in >=5 meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "101",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant segragates in >=3 meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637787",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637787",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--J"
},
{
"entContent": {
"_uniqueProp": "002_BP4_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "002",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "116",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637786",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637786",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--I"
},
{
"entContent": {
"_uniqueProp": "002_BP3_nuclear_MYH7",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "002",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637784",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637784",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--I"
},
{
"entContent": {
"_uniqueProp": "002_BP2_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "002",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "118",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed as comp het (in trans) or double het in genes with overlapping function (e.g. sarcomere genes) without increased disease severity -OR- Observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637782",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637782",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--Q"
},
{
"entContent": {
"_uniqueProp": "002_BS4_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "002",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "121",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation in affected members of a family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637779",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637779",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--G"
},
{
"entContent": {
"_uniqueProp": "002_BS1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Population Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "002",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "120",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637772",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637772",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--C"
},
{
"entContent": {
"_uniqueProp": "002_PS1_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "002",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "110",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Different nucleotide change (same amino acid) as a previously established pathogenic variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637781",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637781",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--P"
},
{
"entContent": {
"_uniqueProp": "002_BS3_nuclear_MYH7",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0005201",
"MONDO:0009144"
],
"evidenceCategory": "Functional Data",
"gene": [
"MYH7"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "002",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "122",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637776",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637776",
"modified": "2022-01-19T20:33:33.109Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--D"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005045",
"lbl": "hypertrophic cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5962"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypertrophic_cardiomyopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_hypertrophic_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020871"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1830681485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2881"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002312"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/233873004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_11984"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34449"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000538"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#narrowMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#relatedMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
}
],
"definition": {
"val": "A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.",
"xrefs": [
"NCIT:C34449"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hypertrophic cardiomyopathy",
"xrefs": [
"DOID:11984",
"NCIT:C34449",
"icd11.foundation:1830681485"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic obstructive cardiomyopathy",
"xrefs": [
"DOID:11984"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic subaortic stenosis"
},
{
"pred": "hasExactSynonym",
"val": "obstructive hypertrophic cardiomyopathy"
},
{
"pred": "hasNarrowSynonym",
"val": "familial hypertrophic cardiomyopathy"
},
{
"pred": "hasRelatedSynonym",
"val": "HCM - hypertrophic cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:11984"
},
{
"val": "EFO:0000538"
},
{
"val": "HP:0001639"
},
{
"val": "ICD10CM:I42.1"
},
{
"val": "ICD10CM:I42.2"
},
{
"val": "ICD9:425.1"
},
{
"val": "ICD9:425.11"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2881"
},
{
"val": "MESH:D002312"
},
{
"val": "MedDRA:10020871"
},
{
"val": "NANDO:1200286"
},
{
"val": "NANDO:1200288"
},
{
"val": "NANDO:2100054"
},
{
"val": "NANDO:2200229"
},
{
"val": "NANDO:2201042"
},
{
"val": "NCIT:C34449"
},
{
"val": "Orphanet:217569"
},
{
"val": "SCTID:233873004"
},
{
"val": "UMLS:C0007194"
},
{
"val": "icd11.foundation:1830681485"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005045",
"name": "hypertrophic cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005045",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005045",
"entType": "Disease",
"ldhId": "135641999",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641999",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9FG---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005021",
"lbl": "dilated cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005021"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/dilated_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10056370"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1916294688"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2880"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002311"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/195021004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007193"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.0"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12930"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84673"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000407"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217604"
}
],
"definition": {
"val": "Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "dilated cardiomyopathy",
"xrefs": [
"DOID:12930",
"ICD10CM:I42.0",
"NCIT:C84673",
"Orphanet:217604",
"icd11.foundation:1916294688"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congestive cardiomyopathy",
"xrefs": [
"DOID:12930"
]
},
{
"pred": "hasRelatedSynonym",
"val": "familial dilated cardiomyopathy",
"xrefs": [
"DOID:12930",
"MESH:C536231"
]
},
{
"pred": "hasRelatedSynonym",
"val": "idiopathic dilation cardiomyopathy",
"xrefs": [
"DOID:12930",
"MESH:C536277"
]
},
{
"pred": "hasRelatedSynonym",
"val": "primary dilated cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:12930"
},
{
"val": "EFO:0000407"
},
{
"val": "GARD:221"
},
{
"val": "HP:0001644"
},
{
"val": "ICD10CM:I42.0"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2880"
},
{
"val": "MESH:D002311"
},
{
"val": "MedDRA:10056370"
},
{
"val": "NANDO:2100057"
},
{
"val": "NANDO:2200232"
},
{
"val": "NCIT:C84673"
},
{
"val": "Orphanet:217604"
},
{
"val": "SCTID:195021004"
},
{
"val": "UMLS:C0007193"
},
{
"val": "icd11.foundation:1916294688"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005021",
"name": "dilated cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005021",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005021",
"entType": "Disease",
"ldhId": "135641998",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641998",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9_S---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0004994",
"lbl": "cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10007636"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/282225286"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/209232"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/85898001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0878544"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050700"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34830"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000318"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_167848"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://icd.who.int/browse10/2019/en#/I42"
}
],
"definition": {
"val": "A disease of the heart muscle or myocardium proper. Cardiomyopathies may be classified as either primary or secondary, on the basis of etiology, or on the pathophysiology of the lesion: hypertrophic, dilated, or restrictive.",
"xrefs": [
"NCIT:C34830"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Cardiomyopathies",
"xrefs": [
"DOID:0050700",
"MESH:D009202"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiomyopathy",
"xrefs": [
"DOID:0050700",
"ICD10CM:I42",
"MONDO:0015670",
"NCIT:C34830",
"icd11.foundation:282225286"
]
}
],
"xrefs": [
{
"val": "DOID:0050700"
},
{
"val": "EFO:0000318"
},
{
"val": "ICD10CM:I42"
},
{
"val": "ICD10WHO:I42"
},
{
"val": "ICD9:425"
},
{
"val": "ICD9:425.4"
},
{
"val": "ICD9:425.9"
},
{
"val": "MEDGEN:209232"
},
{
"val": "MESH:D009202"
},
{
"val": "MedDRA:10007636"
},
{
"val": "NCIT:C34830"
},
{
"val": "Orphanet:167848"
},
{
"val": "SCTID:57809008"
},
{
"val": "SCTID:85898001"
},
{
"val": "UMLS:C0878544"
},
{
"val": "icd11.foundation:282225286"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0004994",
"name": "cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0004994",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0004994",
"entType": "Disease",
"ldhId": "135641997",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641997",
"modified": "2025-10-07T15:42:51.624Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U8DS---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009144",
"lbl": "Ebstein anomaly",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000589",
"val": "Ebstein anomaly (disease)"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/ebstein_anomaly"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005561"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0018797"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10014075"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/307157712"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/4435"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D004437"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0013481"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/Q22.5"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_14289"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84681"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0007244"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1880"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/224700"
}
],
"definition": {
"val": "Ebstein's malformation is a rare congenital cardiac anomaly characterized by rotational displacement of the septal and inferior leaflets of the tricuspid valve such that they are hinged within the right ventricle, rather than as expected at the atrioventricular junction.",
"xrefs": [
"Orphanet:1880"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_morphological_anomaly",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Ebstein anomaly",
"xrefs": [
"DOID:14289",
"NCIT:C84681",
"OMIM:224700",
"icd11.foundation:307157712"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein anomaly (disease)",
"xrefs": [
"https://orcid.org/0000-0002-6601-2165"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein anomaly of the tricuspid valve",
"xrefs": [
"Orphanet:1880"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein's anomaly",
"xrefs": [
"DOID:14289",
"ICD9CM:746.2",
"NCIT:C84681"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein's anomaly (disorder) [ambiguous]"
},
{
"pred": "hasExactSynonym",
"val": "Ebstein's anomaly of common atrioventricular valve",
"xrefs": [
"DOID:14289"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein's anomaly of right atrioventricular valve",
"xrefs": [
"DOID:14289"
]
},
{
"pred": "hasExactSynonym",
"val": "Ebstein's anomaly of tricuspid valve",
"xrefs": [
"DOID:14289",
"NCIT:C84681"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ebstein malformation"
},
{
"pred": "hasRelatedSynonym",
"val": "Ebstein's malformation",
"xrefs": [
"GARD:0006313"
]
}
],
"xrefs": [
{
"val": "DOID:14289"
},
{
"val": "EFO:0007244"
},
{
"val": "GARD:6313"
},
{
"val": "ICD10CM:Q22.5"
},
{
"val": "ICD9:746.2"
},
{
"val": "MEDGEN:4435"
},
{
"val": "MESH:D004437"
},
{
"val": "MedDRA:10014075"
},
{
"val": "NANDO:1200711"
},
{
"val": "NANDO:2100080"
},
{
"val": "NANDO:2200260"
},
{
"val": "NCIT:C84681"
},
{
"val": "OMIM:224700"
},
{
"val": "Orphanet:1880"
},
{
"val": "UMLS:C0013481"
},
{
"val": "icd11.foundation:307157712"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009144",
"name": "Ebstein anomaly",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0009144",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009144",
"entType": "Disease",
"ldhId": "135642000",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642000",
"modified": "2025-10-07T15:43:51.748Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V2li---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005201",
"lbl": "restrictive cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/restrictive_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10038748"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/316495940"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/40111"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002313"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/415295002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007196"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_397"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C62798"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0002630"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217632"
}
],
"definition": {
"val": "A type of heart disorder referring to the inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and looses its flexibility. Causes include replacement of the myocardium with scar tissue, abnormal cellular infiltration of the myocardium, or deposition of a substance (e.g., amyloid) in the myocardium.",
"xrefs": [
"NCIT:C62798"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "cardiomyopathy, constrictive",
"xrefs": [
"DOID:397"
]
},
{
"pred": "hasExactSynonym",
"val": "primary restrictive cardiomyopathy",
"xrefs": [
"DOID:397"
]
},
{
"pred": "hasExactSynonym",
"val": "restrictive cardiomyopathy",
"xrefs": [
"DOID:397",
"NCIT:C62798",
"Orphanet:217632",
"icd11.foundation:316495940"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial restrictive cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:397"
},
{
"val": "EFO:0002630"
},
{
"val": "GARD:20531"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:40111"
},
{
"val": "MESH:D002313"
},
{
"val": "MedDRA:10038748"
},
{
"val": "NANDO:1200292"
},
{
"val": "NANDO:1200293"
},
{
"val": "NANDO:2100058"
},
{
"val": "NANDO:2200233"
},
{
"val": "NCIT:C62798"
},
{
"val": "Orphanet:217632"
},
{
"val": "SCTID:415295002"
},
{
"val": "UMLS:C0007196"
},
{
"val": "icd11.foundation:316495940"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005201",
"name": "restrictive cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005201",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005201",
"entType": "Disease",
"ldhId": "135641996",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641996",
"modified": "2025-10-07T15:42:57.134Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7VBF6---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955071365000,
"agr": "HGNC:7577",
"alias_symbol": [
"CMD1S"
],
"ccds_id": [
"CCDS9601"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2016-06-22",
"ena": [
"M58018"
],
"ensembl_gene_id": "ENSG00000092054",
"entrez_id": "4625",
"gene_group": [
"Myosin heavy chains, class II",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
1098,
1691
],
"hgnc_id": "HGNC:7577",
"location": "14q11.2",
"location_sortable": "14q11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"FHC Mutation Database|http://www.angis.org.au/Databases/Heart/heartbreak.html",
"LRG_384|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_384.xml"
],
"mane_select": [
"ENST00000355349.4",
"NM_000257.4"
],
"mgd_id": [
"MGI:2155600"
],
"name": "myosin heavy chain 7",
"omim_id": [
"160760"
],
"orphanet": 123621,
"prev_name": [
"myopathy, distal 1",
"myosin, heavy polypeptide 7, cardiac muscle, beta"
],
"prev_symbol": [
"CMH1",
"MPD1"
],
"pubmed_id": [
2494889,
8483915,
15322983
],
"refseq_accession": [
"NM_000257"
],
"rgd_id": [
"RGD:62030"
],
"status": "Approved",
"symbol": "MYH7",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wjx.4",
"uniprot_ids": [
"P12883"
],
"uuid": "6a9c6657-136d-48c3-be6c-5a823ad924b8",
"vega_id": "OTTHUMG00000028755"
},
"NCBI": {
"id": "4625"
}
},
"entId": "MYH7",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7577",
"entType": "Gene",
"ldhId": "135641799",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641799",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "002_nuclear_MYH7",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0005201",
"MONDO:0004994",
"MONDO:0005021",
"MONDO:0005045",
"MONDO:0009144"
]
}
],
"gene": "MYH7"
}
],
"ns": "002"
},
"entType": "RuleSet",
"ldhId": "135640453",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640453",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--C"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2017-04-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cardiomyopathy",
"shortBaseName": "CMP",
"shortTitle": "Cardiomyopathy VCEP",
"title": "Cardiomyopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50002",
"entIri": "http://clinicalgenome.org/affiliation/50002",
"entType": "Organization",
"ldhId": "135637627",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637627",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--U"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637574",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637574",
"modified": "2025-09-04T17:37:34.296Z",
"modifier": "cspecAdministrator",
"rev": "_kPVMGDy--A"
},
{
"entContent": {
"approvedOn": "2024-03-14T15:55:27.954Z",
"description": "ACMG Classification Rules Specified for PTEN Variant Curation",
"namespace": "GN003",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/30311380"
}
],
"releaseNotes": "Minor Changes: \n1\\. Correct SpliceAI cutoff for BP4 rule \n2\\. Correct the Rules for Combining Criteria \n3\\. Add BLOSUM matrix, Cleveland Clinic core and Pediatric score tables",
"releasedUnderRevision": true,
"shortTitle": "ACMG-PTEN Variant Curation Guideline",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "shengany",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-14T15:55:27.954Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "shengany",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-04T20:35:28.682Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "shengany",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-04T21:12:32.177Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-23T20:17:15.118Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "proberts",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-14T13:32:01.006Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"003"
],
"title": "ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0",
"version": "3.1.0",
"versioned": true
},
"entId": "GN003",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432814",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--O"
},
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432814",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--O"
},
{
"entContent": {
"_uniqueProp": "003_PP2_nuclear_PTEN",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "003",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638188",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638188",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpm---"
},
{
"entContent": {
"_uniqueProp": "003_BP5_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: At least two such cases are required for criteria to apply. In addition, the other gene/disorder must be considered highly penetrant AND the patient’s personal/family history must demonstrate no overlap between the other gene and PTEN.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** At least two such cases are required for criteria to apply. In addition, the other gene/disorder must be considered highly penetrant AND the patient’s personal/family history must demonstrate no overlap between the other gene and _PTEN_.",
"label": "BP5",
"ns": "003",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638186",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638186",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--I"
},
{
"entContent": {
"_uniqueProp": "003_PS4_nuclear_PTEN",
"additionalComments": "Use 1: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nPTEN EP Commentary: This criterion is unlikely to be used in this manner for a condition as rare as PHTS. However, if sufficiently powered, a case-control study finding an odds ratio >2 for a PHTS component phenotype with p<0.05 and 95% confidence interval with lower limit >1.5, this criteria may be applied. However, this criterion may not be applied in combination with PP4.\n\nUse 2: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.\n PTEN EP Specifications: This criterion may not be applied if BS1 applies. Phenotype specificity scores are added across independent probands and calculated as follows:\n * Adults:\n * 1 point per proband with Cleveland Clinic (CC) score >30 (Tan 2011)\n * 0.5 points per proband with CC score of 25-29.\n * Children: 1 point per proband with pediatric phenotype score >5 (please see supplementary information in manuscript for scoring rubric).\n * 0.5 points per proband with pediatric phenotype score of 4, but autism/developmental delay/intellectual disability may not contribute to the score.\nPS4_Very Strong: Probands with specificity score >16.\nPS4: Probands with specificity score of 4-15.5.\nPS4_Moderate: Probands with specificity score of 2-3.5.\nPS4_Supporting: Proband(s) with specificity score of 1-1.5.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Commentary:** This criterion is unlikely to be used in this manner for a condition as rare as PHTS. However, if sufficiently powered, a case-control study finding an odds ratio >2 for a PHTS component phenotype with p\\<0.05 and 95% confidence interval with lower limit >1.5, this criteria may be applied. However, this criterion may _not_ be applied in combination with PP4.\n\n* Use 2: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.\n\n**PTEN EP Specifications:** This criterion may not be applied if BS1 applies. Phenotype specificity scores are added across independent probands and calculated as follows:\n\nAdults: \n\n* 1 point per proband with Cleveland Clinic (CC) score >30 (Tan 2011)\n* 0.5 points per proband with CC score of 25-29.\n\nChildren:\n\n* 1 point per proband with pediatric phenotype score >5 (please see supplementary information in manuscript for scoring rubric).\n* 0.5 points per proband with pediatric phenotype score of 4, but autism/developmental delay/intellectual disability may not contribute to the score.\n\nPS4\\_Very Strong: Probands with specificity score >16.\n\nPS4: Probands with specificity score of 4-15.5.\n\nPS4\\_Moderate: Probands with specificity score of 2-3.5.\n\nPS4\\_Supporting: Proband(s) with specificity score of 1-1.5.",
"label": "PS4",
"ns": "003",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Probands with specificity score ≥16 (see text).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Probands with specificity score of 2-3.5 (see text).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638184",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638184",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--N"
},
{
"entContent": {
"_uniqueProp": "003_PP1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Requires 3 or 4 meioses in order to apply.\nPP1_Strong: At least 7 meioses required across at least two families.\nPP1_Moderate: Requires 5 or 6 meioses in order to apply.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nPP1: Requires 3 or 4 meioses in order to apply.\n\nPP1\\_Strong: At least 7 meioses required across at least two families.\n\nPP1\\_Moderate: Requires 5 or 6 meioses in order to apply.",
"label": "PP1",
"ns": "003",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638183",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638183",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--I"
},
{
"entContent": {
"_uniqueProp": "003_BP6_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432814",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432814",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--O"
},
{
"entContent": {
"_uniqueProp": "003_PM2_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Criteria may be applied if a variant is present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within a subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Please see supplementary information in manuscript supporting application of PM2 for ultra-rare alleles.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Criteria may be applied if a variant is present at \\<0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within a subpopulation, allele frequency in that subpopulation must be \\<0.00002 (0.002%). Please see supplementary information in manuscript supporting application of PM2 for ultra-rare alleles.",
"label": "PM2",
"ns": "003",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent in population\n\n* Databases present at \\<0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be \\<0.00002 (0.002%).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638193",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638193",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqK--F"
},
{
"entContent": {
"_uniqueProp": "003_BP7_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Intronic variants must be positioned at or beyond +7/-21. Nucleotide may be defined as “not conserved” with PhastCons score <1 and PhyloP score <0.1.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Intronic variants must be positioned at or beyond +7/-21.",
"label": "BP7",
"ns": "003",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638190",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638190",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--L"
},
{
"entContent": {
"_uniqueProp": "003_BA1_nuclear_PTEN",
"additioanlComments": "PTEN EP Specification: To be applied for variants with allele frequency >0.01 (>1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Please see supplementary information in manuscript for data supporting this lowered allele frequency threshold.",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "To be applied for variants with filtering allele frequency >0.00056 (>0.056%) in gnomAD. Please see information in BS1 section for data supporting this cutoff.",
"label": "BA1",
"ns": "003",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD Filtering allele frequency >0.00056 (0.056%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638187",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638187",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--H"
},
{
"entContent": {
"_uniqueProp": "003_BP2_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: The other variant may be either pathogenic or likely pathogenic. This rule may also be applied for at least three observations of the variant in cis or unknown phase with different pathogenic or likely pathogenic PTEN variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** The other variant may be either pathogenic or likely pathogenic. This rule may also be applied for at least three observations of the variant _in cis_ or unknown phase with different pathogenic or likely pathogenic _PTEN_ variants.",
"label": "BP2",
"ns": "003",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638178",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638178",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--F"
},
{
"entContent": {
"_uniqueProp": "003_PM6_nuclear_PTEN",
"additionalComments": "PM6_Very Strong: Four or more occurrences of PM6 OR two occurrences of PM6 AND one occurrence of PS2.\nPM6_Strong: Two occurrences of PM6.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "PM6\\_Very Strong: Four or more occurrences of PM6 OR two occurrences of PM6 AND one occurrence of PS2.\n\nPM6\\_Strong: Two occurrences of PM6 OR occurrence of PM6 for an individual with a highly specific phenotype (meets criteria to count towards PS4).\n\n* Of note, when PM6\\_S is applied for a single individual with phenotype specificity, the individual will not be counted towards PS4 as well.",
"label": "PM6",
"ns": "003",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Two probands with presumed _de novo_ occurrence (maternity/ paternity not confirmed) with the disease and no family history.\n\n* May also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype (meets criteria to count towards PS4)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed _de novo,_ but without confirmation of paternity and maternity, in proband with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638176",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638176",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpi--N"
},
{
"entContent": {
"_uniqueProp": "003_BP1_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "003",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638174",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638174",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--K"
},
{
"entContent": {
"_uniqueProp": "003_PM3_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "003",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638169",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638169",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--M"
},
{
"entContent": {
"_uniqueProp": "003_BS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: To be applied for variants with allele frequency of 0.001 up to 0.01 (0.1% up to 1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Please see supplementary information in manuscript for data supporting this lowered allele frequency threshold.\nBS1_Supporting: To be applied for variants with allele frequency of 0.000043 up to 0.001 (0.0043% up to 0.1%) in a studied population with >2,000 alleles tested and variant present in >5 alleles. Threshold based on the approach published by Whiffin et al. (PMID 28518168) using the following values:\n * Prevalence: 1 in 9,000 (based on 15 disease-associated alleles present among the gnomAD population of ~135,000 individuals)\n * Allelic heterogeneity: 22/282 (based on prevalence of most common pathogenic PTEN variants, p.R130X and p.R335X, per Tan et al. PMID 21194675 and Bubien 2013 PMID 23335809)\n *Penetrance: 10% (overall cancer by age 40 for men with pathogenic germline PTEN variants is approximately 20% per Bubien 2013 PMID 23335809).",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nBS1: To be applied for variants with filtering allele frequency of 0.000043 up to 0.00056 (0.0043% up to 0.056%) in gnomAD. \n\nBS1\\_Supporting: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. \n\nBA1, BS1, and BS1\\_P thresholds are based on the approach published by Whiffin et al. (PMID 28518168) using the following values:\n\n* Prevalence: 1 in 9,000 (based on 15 disease-associated alleles present among the gnomAD population of ~135,000 individuals)\n* Allelic heterogeneity: 22/282 (based on prevalence of most common pathogenic _PTEN_ variants, p.R130X and p.R335X, per Tan et al. PMID 21194675 and Bubien 2013 PMID 23335809)\n* Penetrance: 10% (overall cancer by age 40 for men with pathogenic germline _PTEN_ variants is approximately 20% per Bubien 2013 PMID 23335809)\n\nUsing these data points results in a BS1 value of 0.000043. BA1 was calculated by setting allelic heterogeneity to 1, and BS1\\_P by reducing BS1 by an order of magnitude.",
"label": "BS1",
"ns": "003",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638168",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638168",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--E"
},
{
"entContent": {
"_uniqueProp": "003_PP4_nuclear_PTEN",
"additionalComments": "PTEN EP Commentary: Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "003",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638191",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638191",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqK--E"
},
{
"entContent": {
"_uniqueProp": "003_BP4_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict no splicing impact. Not to be applied for variants which may impact the intron 1 splice donor or acceptor sites, and to be used cautiously for variants which may impact the intron 6 splice acceptor.\nPTEN EP Commentary: Please see PP3 commentary.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict no splicing impact (SpliceAl: scores 0-0.2 are considered evidence of benign. VarSeak: Class 1 and 2 are considered evidence of benign). Not to be applied for variants which may impact the intron 1 splice donor or acceptor sites, and to be used cautiously for variants which may impact the intron 6 splice acceptor. May also be applied to missense variants with REVEL score \\< 0.5.\n\n**PTEN EP Commentary:** Per Bayesian adaptation of the ACMG/AMP variant interpretation framework (Tavtigian et al., 2018), odds of pathogenicity (OddsPath) were estimated for various numbers of previously classified controls. When REVEL scores > 0.7 were used as evidence of pathogenic and \\< 0.5 were used as evidence of benign, the oddsPath was equated with moderate evidence strength for benign conditions. Given that the VCEP also applies PP2 for missense variants, we decided to downgrade the evidence strength to be used at a supporting level.",
"label": "BP4",
"ns": "003",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product. \n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL scores \\< 0.5",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638182",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638182",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqK--A"
},
{
"entContent": {
"_uniqueProp": "003_PS3_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: PS3 may be applied to the following assays:\n * In vitro or in vivo assay demonstrating >50% reduction in phosphatase activity compared to wild type control. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S, as well as at least three biological replicates (Myers 1998, Stambolic 1998, Han 2000, Rodriguez-Escudero 2011, Costa 2015, Malek 2017).\n * RNA, mini-gene, or other assay demonstrating an impact on splicing.\n\nPS3_Supporting: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3. Examples of in vitro cellular assays to be considered for PS3_supporting evidence may include:\n * Decreased PTEN or increased pAKT expression (Tan 2011, Spinelli 2015).\n * Disruption of protein cellular localization (Lobo 2009, He 2012, Gil 2015).\n * Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion (Costa 2015, Malek 2017)",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** \n\nPS3 may be applied to the following assays:\n\n* RNA, mini-gene, or other assay demonstrating an impact on splicing.\n\nPS3\\_Moderate: \n\n* Mighell et al. 2018 (PMID: 29706350): Massively parallel functional assay interrogating phosphatase activity. \n * In the supplementary material (Table S2) search for the variant in columns A or B and make sure the variant in question is listed as TRUE under column I (high confidence). If not, do not use as evidence.\n * Under column G, the cumulative score is listed. Apply PS3\\_moderate for all variants with scores \\< -1.11.\n\nPS3\\_Supporting: Other studies demonstrating lipid phosphatase activity \\<50% of wild-type or abnormal _in vitro_ cellular assay or transgenic model with phenotype different from wild-type that does not meet PS3\\_moderate. Examples of _in vitro_ cellular assays to be considered for PS3\\_supporting evidence may include:\n\n* _In vitro_ assay demonstrating >50% reduction in phosphatase activity compared to wild type control. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S, as well as at least three biological replicates: Myers et al. 1998 (PMID: 9811831), Stambolic et al. 1998 (PMID: 9778245), Han et al. 2000 (PMID: 10866302), Rodriguez-Escudero et al. 2011 (PMID: 21828076), Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325).\n* Decreased PTEN or increased pAKT expression: Tan 2011 (PMID: 21194675), Spinelli 2015 (PMID: 25527629).\n* Disruption of protein cellular localization: Lobo et al. 2009 (PMID: 19457929), He et al. 2012 (PMID: 22962422), Gil et al. 2015 (PMID: 25875300)\n* Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion: Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325)",
"label": "PS3",
"ns": "003",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* RNA, mini-gene, or other assay shows impact on splicing",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect on the gene or gene product.\n\n* Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phosphatase activity \\<50% of wild-type or abnormal _in vitro_ cellular assay or transgenic model with phenotype different from wild type that does not meet PS3\\_moderate.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638181",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638181",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--K"
},
{
"entContent": {
"_uniqueProp": "003_BS4_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Two or more families are require for strong evidence level.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:**\n\nBS4: Two or more families are require for strong evidence level.\n\nBS4\\_Supporting: Lack of segregation in one family.",
"label": "BS4",
"ns": "003",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of two or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of one family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638175",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638175",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpi--P"
},
{
"entContent": {
"_uniqueProp": "003_PM4_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: For in-frame insertions or deletions, criteria may apply only if the variant impacts at least one residue in one of the catalytic motifs specified in the PM1 criteria. Criteria will also apply for variants resulting in truncation 3’ to c.1121 (NM_000314.6) or variants resulting in protein extension.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** For in-frame insertions or deletions, criteria may apply only if the variant impacts at least one residue in one of the catalytic motifs specified in the PM1 criteria. Criteria will also apply for variants resulting in protein extension.",
"label": "PM4",
"ns": "003",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638171",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638171",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpy--J"
},
{
"entContent": {
"_uniqueProp": "003_BS2_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: Variant must be observed in the homozygous state in a healthy or PHTS-unaffected individual. Two independent observations are required if the homozygous status is not confirmed via parental testing. If BS1 is also applied, this criteria will be applied at the supporting evidence level to avoid a variant reaching benign status solely based on homozygous occurrences due to high population frequency (BS1+BS2).\nBS2_Supporting: Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** \n\nBS2: Variant must be observed in the homozygous state in a healthy or PHTS-unaffected individual. Two independent observations are required if the homozygous status is not confirmed via parental testing. If BS1 is also applied, this criteria will be applied at the supporting evidence level to avoid a variant reaching benign status solely based on homozygous occurrences due to high population frequency (BS1+BS2).\n\nBS2\\_Supporting: Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"label": "BS2",
"ns": "003",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638170",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638170",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--I"
},
{
"entContent": {
"_uniqueProp": "003_PM1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: Defined to include residues in one of PTEN’s catalytic motifs, which include the WPD loop (residues 90-94), P-loop (also described as phosphatase core, residues 123-130), and the TI-loop (residues 166-168) (NP_ 000305.3) (Lee 1999).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Defined to include residues in one of PTEN’s catalytic motifs, which include the WPD loop (residues 90-94), P-loop (also described as phosphatase core, residues 123-130), and the TI-loop (residues 166-168) (NP\\_ 000305.3) (Lee 1999).",
"label": "PM1",
"ns": "003",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638192",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638192",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqK--C"
},
{
"entContent": {
"_uniqueProp": "003_PS2_nuclear_PTEN",
"additionalComments": "",
"additonalComments": "PS2_Very Strong: Two or more occurrences of PS2 OR two or more occurrences of PM6 AND one occurrence of PS2.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "PS2\\_Very Strong: Two or more occurrences of PS2 OR two or more occurrences of PM6 AND one occurrence of PS2.",
"label": "PS2",
"ns": "003",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638179",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638179",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--N"
},
{
"entContent": {
"_uniqueProp": "003_PS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: PS1 will be applied as described and expanded to include a different nucleotide substitution for an intronic splice site variant if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tools. Caution should be used when applying this criteria to exonic variants causing aberrant splicing.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** PS1 will be applied as described and expanded to include a different nucleotide substitution for an intronic splice site variant if the predicted impact is equal to or greater than the known pathogenic variant per _in silico_ splicing tools. Caution should be used when applying this criteria to exonic variants causing aberrant splicing.",
"label": "PS1",
"ns": "003",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638177",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638177",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpi--M"
},
{
"entContent": {
"_uniqueProp": "003_BS3_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications: BS3 may be applied to the following assays:\n * For missense variants: Lipid phosphatase activity comparable to wild type in addition to a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S (NP_ 000305.3), as well as at least three biological replicates (Myers 1998, Stambolic 1998, Han 2000, Rodriguez-Escudero 2011, Costa 2015, Malek 2017). Examples of second assays may include:\n * Decreased PTEN or increased pAKT expression (Tan 2011, Spinelli 2015).\n * Disruption of protein cellular localization (Lobo 2009, He 2012, Gil 2015).\n * Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion (Costa 2015, Malek 2017).\n * For intronic or synonymous variants: RNA, mini-gene, or other assay demonstrate no impact on splicing.\n BS3_Supporting: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:** \n\nBS3: For intronic or synonymous variants: RNA, mini-gene, or other assay demonstrate no impact on splicing.\n\nBS3\\_Supporting: _In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function.\n\n**PTEN EP Specifications:** BS3\\_supporting may be applied to the following assays:\n\n* Mighell et al. 2018 (PMID: 29706350): Massively parallel functional assay interrogating phosphatase activity. \n * In the supplementary material (Table S2) search for the variant in columns A or B and make sure the variant in question is listed as TRUE under column I (high confidence). If not, do not use as evidence.\n * Under column G, the cumulative score is listed. Apply BS3\\_supporting for all variants with scores > 0.\n* For missense variants: Other studies showing lipid phosphatase activity comparable to wild type in addition to a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. Phosphatase assays for which criteria may be applied must include a catalytic dead control, such as p.C124S (NP\\_ 000305.3), as well as at least three biological replicates: Myers et al. 1998 (PMID: 9811831), Stambolic et al. 1998 (PMID: 9778245), Han et al. 2000 (PMID: 10866302), Rodriguez-Escudero et al. 2011 (PMID: 21828076), Costa et al. 2015 (PMID: 26504226), Malek et al. 2017 (PMID: 29056325)\n* Examples of second assays may include:\n * Decreased PTEN or increased pAKT expression: Tan et al. 2011 (PMID: 21194675), Spinelli et al. 2015 (PMID: 25527629).\n * Disruption of protein cellular localization: Lobo et al. 2009 (PMID: 19457929), He et al. 2012 (PMID: 22962422), Gil et al. 2015 (PMID: 25875300).\n * Aberrant cellular phenotypes, including defective cell migration, proliferation, and invasion: Costa et al. 2015 (PMID: 26504226)\n * Malek et al. 2017 (PMID: 29056325).",
"label": "BS3",
"ns": "003",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established _in vitro_ or _in vivo_ functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "_In vitro_ or _in vivo_ functional study or studies showing no damaging effect on protein function.\n\n* Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638172",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638172",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--M"
},
{
"entContent": {
"_uniqueProp": "003_PP5_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432815",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432815",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--G"
},
{
"entContent": {
"_uniqueProp": "003_PP5_nuclear_PTEN",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "003",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432815",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432815",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqC--G"
},
{
"entContent": {
"_uniqueProp": "003_PP3_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict a splicing impact. Not to be applied for variants which may impact the intron 1 splice donor or acceptor sites, and to be used cautiously for variants which may impact the intron 6 splice acceptor.\nPTEN EP Commentary: Given the lack of known benign or likely benign PTEN missense variants, the Expert Panel was unable to test the accuracy of in silico predictors to be used as evidence to apply BP4 or PP3 for PTEN missense variants. While investigating potential in silico tools, the Expert Panel also came to find that some algorithm predictions were highly sensitive to sequence alignment, further limiting confidence in these tools. Should the Expert Panel classify several missense variants as benign or likely benign, another attempt will be made to validate in silico tools to apply PP3/BP4 for missense variants. Please see supplementary information in manuscript detailing validation of splicing in silico tools and challenges presented by the specified donor/acceptor sites.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** To be applied to synonymous or intronic variants where SpliceAl and VarSeak _in silico_ models predict a splicing impact (SpliceAl: scores 0.5-1 are consider evidence of pathogenic. VarSeak: Class 4 and 5 are consider evidence of pathogenic). May also be applied to missense variants with REVEL score > 0.7.\n\n**PTEN EP Commentary:** Per Bayesian adaptation of the ACMG/AMP variant interpretation framework (Tavtigian et al., 2018), odds of pathogenicity (OddsPath) were estimated for various numbers of previously classified controls. When REVEL scores > 0.7 were used as evidence of pathogenic and \\< 0.5 were used as evidence of benign, the oddsPath was equated with moderate evidence strength for pathogenic conditions. Given that the VCEP also applies PP2 for missense variants, we decided to downgrade the evidence strength to be used at a supporting level.",
"label": "PP3",
"ns": "003",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* Splicing variants: Concordance of SpliceAl and VarSeak\n* Missense variants: REVEL score > 0.7",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638189",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638189",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxqK--B"
},
{
"entContent": {
"_uniqueProp": "003_PVS1_nuclear_PTEN",
"additionalComments": "PTEN EP Specification: For nonsense or frameshift variants at the 3’ end of the gene NOT predicted to result in nonsense-mediated decay, PVS1 may still be applied if the protein is disrupted at or 5’ to c.1121 (NM_000314.6). Please see supplementary information in manuscript for evidence supporting this cutoff.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specification:** Follow SVI guidance, using PTEN-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID 30192042), the following will apply:\n\n1. Nonsense, frameshift variants:\n * PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for PTEN occurs at c.1121 (p.D375).\n * For nonsense or frameshift variants at the 3’ end of the gene NOT predicted to result in nonsense-mediated decay, PVS1 may still be applied if the protein is disrupted at or 5’ to c.1121 (NM\\_000314.6). Please see supplementary information in manuscript for evidence supporting this cutoff.\n * PVS1\\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff.\n2. Splicing variants (+/- 1,2 intronic positions): \n * Only apply to the variants resulting NMD (please refer to decision tree) OR entire exon deletion: \n * Exons 1,2,4,5,6 OR 7 deletions OR multi-exon deletion: PVS1 (Resulting frameshift)\n * Exons 3,8 OR 9 deletions: PVS1\\_Strong (in-frame but truncated/altered region is critical to protein function).\n3. Deletion (Single/multi exon to full gene): Please refer to decision tree.\n4. Duplication: Please refer to decision tree.\n5. Initiation codon: PVS1 applies to initiation codon variants.\n\n**PTEN EP Commentary:** No known alternative start codon in other transcripts. There are sufficient patients’ data from literature and labs support the pathogenicity of initiation codon variants.",
"label": "PVS1",
"ns": "003",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PTEN PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638185",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638185",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--J"
},
{
"entContent": {
"_uniqueProp": "003_BP3_nuclear_PTEN",
"additionalComments": "This rule is not applicable to PTEN.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "003",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638180",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638180",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpi--O"
},
{
"entContent": {
"_uniqueProp": "003_PM5_nuclear_PTEN",
"additionalComments": "PTEN EP Specifications:\n * This rule may be applied when the known variant is likely pathogenic unless applying would lead to a higher (pathogenic) classification for the variant being assessed.\n * The variant in question need not be novel but must have a BLOSUM62 (Henikoff 1992) score equal to or less than the known variant.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PTEN"
],
"geneType": "nuclear",
"instructionsToUse": "**PTEN EP Specifications:**\n\n* This rule may be applied when the known variant is likely pathogenic unless applying would lead to a higher (pathogenic) classification for the variant being assessed.\n* The variant in question need not be novel but must have a BLOSUM62 (Henikoff 1992) score equal to or less than the known variant.",
"label": "PM5",
"ns": "003",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638173",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638173",
"modified": "2024-03-14T15:55:28.606Z",
"modifier": "shengany",
"rev": "_h6SHxpK--L"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0017623",
"lbl": "PTEN hamartoma tumor syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9178"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0017623"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019300"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/12800/pten-hamartoma-tumor-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/368366"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/722859001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1959582"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080191"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179915"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_306498"
}
],
"definition": {
"val": "An autosomal dominant syndrome caused by pathogenic variants in the PTEN gene, characterized by hamartomas, overgrowth, neurodevelopmental disorders and an increased risk of various cancers, including breast, thyroid, and endometrial cancer. PHTS encompasses Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome.",
"xrefs": [
"Orphanet:306498",
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PHTS",
"xrefs": [
"NCIT:C179915",
"Orphanet:306498"
]
},
{
"pred": "hasExactSynonym",
"val": "PTEN hamartoma tumor syndrome",
"xrefs": [
"DOID:0080191",
"NCIT:C179915",
"Orphanet:306498"
]
},
{
"pred": "hasExactSynonym",
"val": "PTEN-related Hamartoma tumor syndrome",
"xrefs": [
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
}
],
"xrefs": [
{
"val": "DOID:0080191"
},
{
"val": "GARD:12800"
},
{
"val": "MEDGEN:368366"
},
{
"val": "NCIT:C179915"
},
{
"val": "NORD:1631"
},
{
"val": "Orphanet:306498"
},
{
"val": "SCTID:722859001"
},
{
"val": "UMLS:C1959582"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0017623",
"name": "PTEN hamartoma tumor syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0017623",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0017623",
"entType": "Disease",
"ldhId": "135642014",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642014",
"modified": "2025-10-07T15:46:12.685Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YAJ6---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056958559977500,
"agr": "HGNC:9588",
"alias_name": [
"mutated in multiple advanced cancers 1"
],
"alias_symbol": [
"MMAC1",
"TEP1",
"PTEN1"
],
"ccds_id": [
"CCDS31238"
],
"cosmic": "PTEN",
"date_approved_reserved": "1997-04-21",
"date_modified": "2021-05-26",
"date_name_changed": "2008-07-31",
"ena": [
"U92436"
],
"ensembl_gene_id": "ENSG00000171862",
"entrez_id": "5728",
"enzyme_id": [
"3.1.3.16",
"3.1.3.48",
"3.1.3.67"
],
"gene_group": [
"C2 tensin-type domain containing",
"PTEN protein phosphatases",
"Phosphoinositide phosphatases"
],
"gene_group_id": [
837,
902,
1079
],
"hgnc_id": "HGNC:9588",
"iuphar": "objectId:2497",
"location": "10q23.31",
"location_sortable": "10q23.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_311|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_311.xml"
],
"mane_select": [
"ENST00000371953.8",
"NM_000314.8"
],
"mgd_id": [
"MGI:109583"
],
"name": "phosphatase and tensin homolog",
"omim_id": [
"601728"
],
"orphanet": 118128,
"prev_symbol": [
"BZS",
"MHAM"
],
"pubmed_id": [
9090379
],
"refseq_accession": [
"NM_000314"
],
"rgd_id": [
"RGD:61995"
],
"status": "Approved",
"symbol": "PTEN",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001kfb.4",
"uniprot_ids": [
"P60484"
],
"uuid": "cbd26347-1d2b-4311-a978-b35706b3f294",
"vega_id": "OTTHUMG00000018688"
},
"NCBI": {
"id": "5728"
}
},
"entId": "PTEN",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9588",
"entType": "Gene",
"ldhId": "135641805",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641805",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "003_nuclear_PTEN",
"geneType": "nuclear",
"generalComments": "Minor Changes:\n1. Correct SpliceAI cutoff for BP4 rule \n2. Correct the Rules for Combining Criteria\n3. Add BLOSUM matrix, Cleveland Clinic core and Pediatric score tables",
"genes": [
{
"diseases": [],
"gene": "PTEN"
}
],
"ns": "003",
"references": [
{
"auths": [
"Costa HA",
"Leitner MG",
"et al."
],
"doiStr": "10.1073/pnas.1422504112",
"id": "26504226",
"iss": "(45)",
"namespace": "pmid",
"pages": "p. 13976-81.",
"source": "Proc Natl Acad Sci U S A",
"title": "Discovery and functional characterization of a neomorphic PTEN mutation.",
"vol": "112",
"year": "2015"
},
{
"auths": [
"Gil A",
"Rodríguez-Escudero I",
"et al."
],
"doiStr": "10.1371/journal.pone.0119287",
"id": "25875300",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. e0119287.",
"source": "PLoS One",
"title": "A functional dissection of PTEN N-terminus: implications in PTEN subcellular targeting and tumor suppressor activity.",
"vol": "10",
"year": "2015"
},
{
"auths": [
"Han SY",
"Kato H",
"et al."
],
"doiStr": "",
"id": "10866302",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 3147-51.",
"source": "Cancer Res",
"title": "Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.",
"vol": "60",
"year": "2000"
},
{
"auths": [
"He X",
"Saji M",
"et al."
],
"doiStr": "10.1210/jc.2012-1991",
"id": "22962422",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. E2179-87.",
"source": "J Clin Endocrinol Metab",
"title": "PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.",
"vol": "97",
"year": "2012"
},
{
"auths": [
"Henikoff S",
"Henikoff JG"
],
"doiStr": "10.1073/pnas.89.22.10915",
"id": "1438297",
"iss": "(22)",
"namespace": "pmid",
"pages": "p. 10915-9.",
"source": "Proc Natl Acad Sci U S A",
"title": "Amino acid substitution matrices from protein blocks.",
"vol": "89",
"year": "1992"
},
{
"auths": [
"Lobo GP",
"Waite KA",
"et al."
],
"doiStr": "10.1093/hmg/ddp220",
"id": "19457929",
"iss": "(15)",
"namespace": "pmid",
"pages": "p. 2851-62.",
"source": "Hum Mol Genet",
"title": "Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function.",
"vol": "18",
"year": "2009"
},
{
"auths": [
"Malek M",
"Kielkowska A",
"et al."
],
"doiStr": "10.1016/j.molcel.2017.09.024",
"id": "29056325",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 566-580.e10.",
"source": "Mol Cell",
"title": "PTEN Regulates PI(3,4)P(2) Signaling Downstream of Class I PI3K.",
"vol": "68",
"year": "2017"
},
{
"auths": [
"Mighell TL",
"Evans-Dutson S",
"et al."
],
"doiStr": "10.1016/j.ajhg.2018.03.018",
"id": "29706350",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 943-955.",
"source": "Am J Hum Genet",
"title": "A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.",
"vol": "102",
"year": "2018"
},
{
"auths": [
"Myers MP",
"Pass I",
"et al."
],
"doiStr": "10.1073/pnas.95.23.13513",
"id": "9811831",
"iss": "(23)",
"namespace": "pmid",
"pages": "p. 13513-8.",
"source": "Proc Natl Acad Sci U S A",
"title": "The lipid phosphatase activity of PTEN is critical for its tumor supressor function.",
"vol": "95",
"year": "1998"
},
{
"auths": [
"Richards S",
"Aziz N",
"et al."
],
"doiStr": "10.1038/gim.2015.30",
"id": "25741868",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 405-24.",
"source": "Genet Med",
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.",
"vol": "17",
"year": "2015"
},
{
"auths": [
"Rodríguez-Escudero I",
"Oliver MD",
"et al."
],
"doiStr": "10.1093/hmg/ddr337",
"id": "21828076",
"iss": "(21)",
"namespace": "pmid",
"pages": "p. 4132-42.",
"source": "Hum Mol Genet",
"title": "A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.",
"vol": "20",
"year": "2011"
},
{
"auths": [
"Spinelli L",
"Black FM",
"et al."
],
"doiStr": "10.1136/jmedgenet-2014-102803",
"id": "25527629",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 128-34.",
"source": "J Med Genet",
"title": "Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.",
"vol": "52",
"year": "2015"
},
{
"auths": [
"Stambolic V",
"Suzuki A",
"et al."
],
"doiStr": "10.1016/s0092-8674(00)81780-8",
"id": "9778245",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 29-39.",
"source": "Cell",
"title": "Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.",
"vol": "95",
"year": "1998"
},
{
"auths": [
"Tavtigian SV",
"Greenblatt MS",
"et al."
],
"doiStr": "10.1038/gim.2017.210",
"id": "29300386",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1054-1060.",
"source": "Genet Med",
"title": "Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.",
"vol": "20",
"year": "2018"
},
{
"auths": [
"Tan MH",
"Mester J",
"et al."
],
"doiStr": "10.1016/j.ajhg.2010.11.013",
"id": "21194675",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 42-56.",
"source": "Am J Hum Genet",
"title": "A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands.",
"vol": "88",
"year": "2011"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS3_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PP1",
"PP2",
"PP3"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
}
]
}
},
"entType": "RuleSet",
"ldhId": "135640513",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640513",
"modified": "2024-03-14T15:55:28.514Z",
"modifier": "shengany",
"rev": "_h6SHyTW--o"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2018-08-29T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "PTEN",
"shortBaseName": "PTEN",
"shortTitle": "PTEN VCEP",
"title": "PTEN Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50012",
"entIri": "http://clinicalgenome.org/affiliation/50012",
"entType": "Organization",
"ldhId": "135637636",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637636",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--F"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637575",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637575",
"modified": "2024-03-14T15:55:28.429Z",
"modifier": "shengany",
"rev": "_h6SHykW--M"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "004_BP6_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "004",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432844",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432844",
"modified": "2022-01-19T20:31:29.467Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--N"
},
{
"entContent": {
"_uniqueProp": "004_PM1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Functional Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "004",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PM1 upgraded in strength to Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Analogous Gene",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638354",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638354",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--A"
},
{
"entContent": {
"_uniqueProp": "004_BP7_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "004",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\nThis rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638352",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638352",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--O"
},
{
"entContent": {
"_uniqueProp": "004_PP3_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "004",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638351",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638351",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--_"
},
{
"entContent": {
"_uniqueProp": "004_PS2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PS2_Very Strong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "De novo Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "004",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638341",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638341",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Q"
},
{
"entContent": {
"_uniqueProp": "004_BP2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Allelic Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "004",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638340",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638340",
"modified": "2021-11-05T21:07:12.074Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--C"
},
{
"entContent": {
"_uniqueProp": "004_BP1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "004",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0082",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638336",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638336",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--P"
},
{
"entContent": {
"_uniqueProp": "004_PP2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PP2 is applicable to all RASopathy genes described and curated herein.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Functional Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "004",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PP2 is applicable to all RASopathy genes described and curated herein.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638350",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638350",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--N"
},
{
"entContent": {
"_uniqueProp": "004_BA1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "004",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638349",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638349",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--R"
},
{
"entContent": {
"_uniqueProp": "004_PVS1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "004",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638347",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638347",
"modified": "2022-01-19T20:33:33.485Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--M"
},
{
"entContent": {
"_uniqueProp": "004_BS4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "004",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638337",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638337",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--L"
},
{
"entContent": {
"_uniqueProp": "004_PP4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Other Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "004",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638353",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638353",
"modified": "2022-01-19T20:33:33.485Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy---"
},
{
"entContent": {
"_uniqueProp": "004_BP4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "004",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638344",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638344",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--F"
},
{
"entContent": {
"_uniqueProp": "004_PS3_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Functional Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "004",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638343",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638343",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--C"
},
{
"entContent": {
"_uniqueProp": "004_BP3_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "004",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638342",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638342",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--B"
},
{
"entContent": {
"_uniqueProp": "004_BS3_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Functional Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "004",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638334",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638334",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--C"
},
{
"entContent": {
"_uniqueProp": "004_PM4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "004",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638333",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638333",
"modified": "2021-11-05T21:07:12.074Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--C"
},
{
"entContent": {
"_uniqueProp": "004_BS2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "004",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638332",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638332",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--O"
},
{
"entContent": {
"_uniqueProp": "004_PM2_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "The variant must be completely absent from all population databases.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "004",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The variant must be completely absent from all population databases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638355",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638355",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--S"
},
{
"entContent": {
"_uniqueProp": "004_PS4_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PS4: ≥5 independent occurrences\nPS4_Moderate: ≥3 independent occurrences\nPS4_Supporting: ≥1 independent occurrences",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "004",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 independent occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥3 independent occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥1 independent occurrences.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638346",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638346",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--H"
},
{
"entContent": {
"_uniqueProp": "004_PP1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PP1_Moderate: ≥5 informative meioses\nPP1_Strong: ≥7 informative meioses",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Segregation Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "004",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥7 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.\n≥5 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "General",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638345",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638345",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--G"
},
{
"entContent": {
"_uniqueProp": "004_PM6_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "PM6_Strong: ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.\nPS2_VeryStrong: ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "De novo Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "004",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "None",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638338",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638338",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--M"
},
{
"entContent": {
"_uniqueProp": "004_PM5_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2\n\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "004",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": "Strength",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.\n≥2 different pathogenic missense changes seen before at same residue of missense change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "Analogous Gene",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\nGroup 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2\nThis rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638335",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638335",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--A"
},
{
"entContent": {
"_uniqueProp": "004_PM3_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This criterion is not applicable to the RASopathies.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Allelic Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "004",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not applicable to the RASopathies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638331",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638331",
"modified": "2022-01-19T20:33:33.485Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--B"
},
{
"entContent": {
"_uniqueProp": "004_PP5_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "004",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432845",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432845",
"modified": "2022-01-19T20:31:29.467Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--L"
},
{
"entContent": {
"_uniqueProp": "004_BP5_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Other Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "004",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": "Variant found in a case with an alternate molecular basis for disease",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638348",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638348",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--I"
},
{
"entContent": {
"_uniqueProp": "004_PS1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\n * Group 1: HRAS, NRAS, KRAS\n * Group 2: MAP2K1, MAP2K2\n * Group 3: SOS1, SOS2",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "004",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "Analogous Gene",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:\nGroup 1: HRAS, NRAS, KRAS\n Group 2: MAP2K1, MAP2K2\nGroup 3: SOS1, SOS2",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638339",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638339",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--E"
},
{
"entContent": {
"_uniqueProp": "004_BS1_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"additionalComments": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007893",
"MONDO:0009026",
"MONDO:0015280",
"MONDO:0018997",
"MONDO:0021060",
"MONDO:0054637"
],
"evidenceCategory": "Population Data",
"gene": [
"BRAF",
"HRAS",
"KRAS",
"MAP2K1",
"MAP2K2",
"NRAS",
"PTPN11",
"RAF1",
"RIT1",
"SHOC2",
"SOS1",
"SOS2"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "004",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638330",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638330",
"modified": "2021-11-05T21:11:02.424Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--N"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015280",
"lbl": "cardiofaciocutaneous syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/403770008"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535579"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1275081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS115150"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060233"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84617"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1340"
}
],
"definition": {
"val": "Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), growth retardation and intellectual disability.",
"xrefs": [
"Orphanet:1340"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#clingen"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "CFC",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "CFC syndrome",
"xrefs": [
"DOID:0060233",
"Orphanet:1340"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure",
"xrefs": [
"GARD:0009146"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous (CFC) syndrome",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous syndrome",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "cardio-facial-cutaneous syndrome",
"xrefs": [
"DOID:0060233"
]
},
{
"pred": "hasRelatedSynonym",
"val": "cardio-facio-cutaneous syndrome",
"xrefs": [
"GARD:0009146"
]
}
],
"xrefs": [
{
"val": "MESH:C535579"
},
{
"val": "SCTID:403770008"
},
{
"val": "DOID:0060233"
},
{
"val": "Orphanet:1340"
},
{
"val": "OMIMPS:115150"
},
{
"val": "GARD:0009146"
},
{
"val": "UMLS:C1275081"
},
{
"val": "NCIT:C84617"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015280",
"name": "cardiofaciocutaneous syndrome"
},
"entId": "MONDO:0015280",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015280",
"entType": "Disease",
"ldhId": "135642043",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642043",
"modified": "2023-01-27T21:42:28.275Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzNm--H"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015280",
"lbl": "cardiofaciocutaneous syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/403770008"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535579"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1275081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS115150"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060233"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84617"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1340"
}
],
"definition": {
"val": "Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), growth retardation and intellectual disability.",
"xrefs": [
"Orphanet:1340"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#clingen"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "CFC",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "CFC syndrome",
"xrefs": [
"DOID:0060233",
"Orphanet:1340"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure",
"xrefs": [
"GARD:0009146"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous (CFC) syndrome",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous syndrome",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "cardio-facial-cutaneous syndrome",
"xrefs": [
"DOID:0060233"
]
},
{
"pred": "hasRelatedSynonym",
"val": "cardio-facio-cutaneous syndrome",
"xrefs": [
"GARD:0009146"
]
}
],
"xrefs": [
{
"val": "MESH:C535579"
},
{
"val": "SCTID:403770008"
},
{
"val": "DOID:0060233"
},
{
"val": "Orphanet:1340"
},
{
"val": "OMIMPS:115150"
},
{
"val": "GARD:0009146"
},
{
"val": "UMLS:C1275081"
},
{
"val": "NCIT:C84617"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015280",
"name": "cardiofaciocutaneous syndrome"
},
"entId": "MONDO:0015280",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015280",
"entType": "Disease",
"ldhId": "135642041",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642041",
"modified": "2023-01-27T21:42:28.275Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzNu--B"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009026",
"lbl": "Costello syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5682"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009026"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/costello_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019292"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/1550/costello-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10067380"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1946512039"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/108454"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D056685"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/309776008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0587248"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050469"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84652"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_3071"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/218040"
}
],
"definition": {
"val": "Costello syndrome (CS) is a rare multisystemic disorder characterized by failure to thrive, short stature, developmental delay or intellectual disability, joint laxity, soft skin, and distinctive facial features. Cardiac and neurological involvement is common and there is an increased lifetime risk of certain tumors.",
"xrefs": [
"Orphanet:3071"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Costello syndrome",
"xrefs": [
"DOID:0050469",
"MONDO:Lexical",
"NCIT:C84652",
"OMIM:218040",
"Orphanet:3071",
"icd11.foundation:1946512039"
]
},
{
"pred": "hasExactSynonym",
"val": "FCS syndrome",
"xrefs": [
"DOID:0050469",
"OMIM:218040",
"Orphanet:3071"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital myopathy with excess of muscle spindles"
},
{
"pred": "hasExactSynonym",
"val": "faciocutaneoskeletal syndrome",
"xrefs": [
"DOID:0050469",
"OMIM:218040",
"Orphanet:3071"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CSTLO",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "myopathy, congenital, with excess of muscle spindles"
}
],
"xrefs": [
{
"val": "DOID:0050469"
},
{
"val": "GARD:1550"
},
{
"val": "ICD9:799.89"
},
{
"val": "MEDGEN:108454"
},
{
"val": "MESH:D056685"
},
{
"val": "MedDRA:10067380"
},
{
"val": "NANDO:1200463"
},
{
"val": "NANDO:2200971"
},
{
"val": "NCIT:C84652"
},
{
"val": "NORD:1011"
},
{
"val": "OMIM:218040"
},
{
"val": "Orphanet:3071"
},
{
"val": "SCTID:309776008"
},
{
"val": "UMLS:C0587248"
},
{
"val": "icd11.foundation:1946512039"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009026",
"name": "Costello syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0009026",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009026",
"entType": "Disease",
"ldhId": "135642038",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642038",
"modified": "2025-10-07T15:43:50.286Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V1G----"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015280",
"lbl": "cardiofaciocutaneous syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015280"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/266149"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535579"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/403770008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1275081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060233"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84617"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1340"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS115150"
}
],
"definition": {
"val": "Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), growth retardation and intellectual disability.",
"xrefs": [
"Orphanet:1340"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CFC",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "CFC syndrome",
"xrefs": [
"DOID:0060233",
"Orphanet:1340"
]
},
{
"pred": "hasExactSynonym",
"val": "cardio-facial-cutaneous syndrome",
"xrefs": [
"DOID:0060233"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous (CFC) syndrome",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "cardiofaciocutaneous syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "cardio-facio-cutaneous syndrome",
"xrefs": [
"GARD:0009146"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure",
"xrefs": [
"GARD:0009146"
]
}
],
"xrefs": [
{
"val": "DOID:0060233"
},
{
"val": "GARD:9146"
},
{
"val": "MEDGEN:266149"
},
{
"val": "MESH:C535579"
},
{
"val": "NANDO:1200462"
},
{
"val": "NANDO:2200967"
},
{
"val": "NCIT:C84617"
},
{
"val": "NORD:891"
},
{
"val": "OMIMPS:115150"
},
{
"val": "Orphanet:1340"
},
{
"val": "SCTID:403770008"
},
{
"val": "UMLS:C1275081"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015280",
"name": "cardiofaciocutaneous syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0015280",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015280",
"entType": "Disease",
"ldhId": "135642033",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642033",
"modified": "2024-11-20T17:52:42.000Z",
"modifier": "cspecAdministrator",
"rev": "_iyoydFu---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642032",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642032",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzoi--W"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007893",
"lbl": "Noonan syndrome with multiple lentigines",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007893"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/noonan_syndrome_with_multiple_lentigines"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10062901"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/104494"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D044542"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/111306001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0175704"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_14291"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84820"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_500"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS151100"
}
],
"definition": {
"val": "A rare multisystem genetic disorder characterized by lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features.",
"xrefs": [
"Orphanet:500",
"https://orcid.org/0000-0001-5208-3432"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome",
"xrefs": [
"DOID:14291"
]
},
{
"pred": "hasExactSynonym",
"val": "Cardiomyopathic lentiginosis",
"xrefs": [
"Orphanet:500"
]
},
{
"pred": "hasExactSynonym",
"val": "Gorlin syndrome II",
"xrefs": [
"DOID:14291"
]
},
{
"pred": "hasExactSynonym",
"val": "LEOPARD syndrome",
"xrefs": [
"DOID:14291",
"MONDO:0001937",
"NCIT:C84820",
"OMIMPS:151100",
"Orphanet:500"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome with multiple lentigines",
"xrefs": [
"DOID:14291",
"Orphanet:500"
]
},
{
"pred": "hasExactSynonym",
"val": "familial multiple lentigines syndrome",
"xrefs": [
"Orphanet:500"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "generalised lentiginosis"
},
{
"pred": "hasExactSynonym",
"val": "generalized lentiginosis",
"xrefs": [
"DOID:14291"
]
},
{
"pred": "hasExactSynonym",
"val": "lentigines, electrocardiographic conduction defects, 0cular hypertelorism, pulmonary stenosis, abnormalities of the genitals, retarded Growth, deafness"
},
{
"pred": "hasExactSynonym",
"val": "lentiginosis profusa syndrome",
"xrefs": [
"DOID:14291"
]
},
{
"pred": "hasExactSynonym",
"val": "progressive cardiomyopathic lentiginosis",
"xrefs": [
"DOID:14291"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Moynahan syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, Deafnes",
"xrefs": [
"GARD:0001100"
]
}
],
"xrefs": [
{
"val": "DOID:14291"
},
{
"val": "GARD:1100"
},
{
"val": "ICD9:709.09"
},
{
"val": "MEDGEN:104494"
},
{
"val": "MESH:D044542"
},
{
"val": "MedDRA:10062901"
},
{
"val": "NCIT:C84820"
},
{
"val": "NORD:1360"
},
{
"val": "OMIMPS:151100"
},
{
"val": "Orphanet:500"
},
{
"val": "SCTID:111306001"
},
{
"val": "UMLS:C0175704"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007893",
"name": "Noonan syndrome with multiple lentigines",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0007893",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007893",
"entType": "Disease",
"ldhId": "135642030",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642030",
"modified": "2025-10-07T15:43:33.109Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vkk----"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0021060"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "GARD:0010955"
},
{
"val": "DOID:3490"
},
{
"val": "ICD9:759.89"
},
{
"val": "NCIT:C34854"
},
{
"val": "MedDRA:10029748"
},
{
"val": "OMIMPS:163950"
},
{
"val": "SCTID:205824006"
},
{
"val": "Orphanet:648"
},
{
"val": "UMLS:C0028326"
},
{
"val": "MESH:D009634"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome"
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642028",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642028",
"modified": "2023-01-27T21:42:39.116Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzd2--J"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642035",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642035",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzoi--X"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0021060"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "GARD:0010955"
},
{
"val": "DOID:3490"
},
{
"val": "ICD9:759.89"
},
{
"val": "NCIT:C34854"
},
{
"val": "MedDRA:10029748"
},
{
"val": "OMIMPS:163950"
},
{
"val": "SCTID:205824006"
},
{
"val": "Orphanet:648"
},
{
"val": "UMLS:C0028326"
},
{
"val": "MESH:D009634"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome"
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642031",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642031",
"modified": "2023-01-27T21:42:39.116Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzd2--K"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0021060"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1792298"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5555857"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080690"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001502"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "RASopathy"
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
}
],
"xrefs": [
{
"val": "DOID:0080690"
},
{
"val": "EFO:1001502"
},
{
"val": "GARD:22213"
},
{
"val": "MEDGEN:1792298"
},
{
"val": "NCIT:C179667"
},
{
"val": "Orphanet:536391"
},
{
"val": "UMLS:C5555857"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642029",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642029",
"modified": "2024-11-20T17:54:52.832Z",
"modifier": "cspecAdministrator",
"rev": "_iyo0cl2---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642039",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642039",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzoi--Y"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0054637",
"lbl": "Noonan syndrome-like disorder with loose anagen hair 1",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/noonan_syndrome_like_disorder_with_loose_anagen_hair_1"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_from_qc_check",
"val": "http://purl.obolibrary.org/obo/mondo/sparql/qc/mondo/qc-omim-subsumption.sparql"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1379805"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C4478716"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080692"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C176939"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/607721"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "NSLH"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "NSLH1",
"xrefs": [
"NCIT:C176939",
"OMIM:607721"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome-like disorder with loose anagen hair 1",
"xrefs": [
"DOID:0080692",
"NCIT:C176939",
"OMIM:607721"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome-like with loose anagen hair 1"
},
{
"pred": "hasRelatedSynonym",
"val": "Tosti syndrome"
}
],
"xrefs": [
{
"val": "DOID:0080692"
},
{
"val": "MEDGEN:1379805"
},
{
"val": "NCIT:C176939"
},
{
"val": "OMIM:607721"
},
{
"val": "UMLS:C4478716"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0054637",
"name": "Noonan syndrome-like disorder with loose anagen hair 1",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0054637",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0054637",
"entType": "Disease",
"ldhId": "135642021",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642021",
"modified": "2025-10-07T15:48:23.923Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aAfC---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642040",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642040",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzpi--Z"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642037",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642037",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzpi---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015280",
"lbl": "cardiofaciocutaneous syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015280"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/cardiofaciocutaneous_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/266149"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535579"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/403770008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1275081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060233"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84617"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1340"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS115150"
}
],
"definition": {
"val": "Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), growth retardation and intellectual disability.",
"xrefs": [
"Orphanet:1340"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CFC",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "CFC syndrome",
"xrefs": [
"DOID:0060233",
"NCIT:C84617",
"Orphanet:1340"
]
},
{
"pred": "hasExactSynonym",
"val": "cardio-facial-cutaneous syndrome",
"xrefs": [
"DOID:0060233"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous (CFC) syndrome",
"xrefs": [
"NCIT:C84617"
]
},
{
"pred": "hasExactSynonym",
"val": "cardiofaciocutaneous syndrome",
"xrefs": [
"DOID:0060233",
"NCIT:C84617",
"OMIMPS:115150",
"Orphanet:1340"
]
},
{
"pred": "hasRelatedSynonym",
"val": "cardio-facio-cutaneous syndrome",
"xrefs": [
"GARD:0009146"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure",
"xrefs": [
"GARD:0009146"
]
}
],
"xrefs": [
{
"val": "DOID:0060233"
},
{
"val": "GARD:9146"
},
{
"val": "MEDGEN:266149"
},
{
"val": "MESH:C535579"
},
{
"val": "NANDO:1200462"
},
{
"val": "NANDO:2200967"
},
{
"val": "NCIT:C84617"
},
{
"val": "NORD:891"
},
{
"val": "OMIMPS:115150"
},
{
"val": "Orphanet:1340"
},
{
"val": "SCTID:403770008"
},
{
"val": "UMLS:C1275081"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015280",
"name": "cardiofaciocutaneous syndrome"
},
"entId": "MONDO:0015280",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015280",
"entType": "Disease",
"ldhId": "135642036",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642036",
"modified": "2025-10-07T15:45:31.122Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XXwu---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0018997"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1044395354"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/18073"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome",
"xrefs": [
"DOID:3490",
"NCIT:C34854",
"OMIMPS:163950",
"Orphanet:648",
"icd11.foundation:1044395354"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "DOID:3490"
},
{
"val": "GARD:10955"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:18073"
},
{
"val": "MESH:D009634"
},
{
"val": "MedDRA:10029748"
},
{
"val": "NANDO:1200680"
},
{
"val": "NANDO:2200413"
},
{
"val": "NCIT:C34854"
},
{
"val": "NORD:1513"
},
{
"val": "OMIMPS:163950"
},
{
"val": "Orphanet:648"
},
{
"val": "SCTID:205824006"
},
{
"val": "UMLS:C0028326"
},
{
"val": "icd11.foundation:1044395354"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome"
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642026",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642026",
"modified": "2025-10-07T15:46:37.358Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YYKy---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642025",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642025",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzoi--V"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0018997"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0021060"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/18073"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1044395354"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "Noonan syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "DOID:3490"
},
{
"val": "GARD:10955"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:18073"
},
{
"val": "MESH:D009634"
},
{
"val": "MedDRA:10029748"
},
{
"val": "NANDO:1200680"
},
{
"val": "NANDO:2200413"
},
{
"val": "NCIT:C34854"
},
{
"val": "NORD:1513"
},
{
"val": "OMIMPS:163950"
},
{
"val": "Orphanet:648"
},
{
"val": "SCTID:205824006"
},
{
"val": "UMLS:C0028326"
},
{
"val": "icd11.foundation:1044395354"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642024",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642024",
"modified": "2024-11-20T17:54:08.081Z",
"modifier": "cspecAdministrator",
"rev": "_iyozwl2---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0021060"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rasopathy"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1792298"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5555857"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080690"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001502"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": [
"DOID:0080690",
"NCIT:C179667",
"Orphanet:536391"
]
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
}
],
"xrefs": [
{
"val": "DOID:0080690"
},
{
"val": "EFO:1001502"
},
{
"val": "GARD:22213"
},
{
"val": "MEDGEN:1792298"
},
{
"val": "NCIT:C179667"
},
{
"val": "Orphanet:536391"
},
{
"val": "UMLS:C5555857"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642023",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642023",
"modified": "2025-10-07T15:47:11.899Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Y6DO---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642020",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642020",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzpi--X"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642042",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642042",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzpi--O"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0021060"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "GARD:0010955"
},
{
"val": "DOID:3490"
},
{
"val": "ICD9:759.89"
},
{
"val": "NCIT:C34854"
},
{
"val": "MedDRA:10029748"
},
{
"val": "OMIMPS:163950"
},
{
"val": "SCTID:205824006"
},
{
"val": "Orphanet:648"
},
{
"val": "UMLS:C0028326"
},
{
"val": "MESH:D009634"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome"
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642034",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642034",
"modified": "2023-01-27T21:42:39.116Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzeG--Q"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642027",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642027",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzpe--w"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021060",
"lbl": "RASopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_536391"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C179667"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
}
],
"definition": {
"val": "Developmental syndromes caused by germline mutations (or in rare cases by somatic mosaicism) in genes that alter the Ras subfamily and mitogen-activated protein kinases that control signal transduction.",
"xrefs": [
"Wikipedia:RASopathy"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "disorder of Ras protein signal transduction",
"xrefs": [
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "RASopathy",
"xrefs": []
},
{
"pred": "hasExactSynonym",
"val": "Ras protein signal transduction disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "Orphanet:536391"
},
{
"val": "NCIT:C179667"
},
{
"val": "EFO:1001502"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021060",
"name": "RASopathy"
},
"entId": "MONDO:0021060",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021060",
"entType": "Disease",
"ldhId": "135642022",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642022",
"modified": "2023-01-27T21:42:44.683Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzoi--U"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949589409800,
"agr": "HGNC:5173",
"ccds_id": [
"CCDS7698",
"CCDS7699"
],
"cosmic": "HRAS",
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2016-06-10",
"ena": [
"AJ437024"
],
"ensembl_gene_id": "ENSG00000174775",
"entrez_id": "3265",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:5173",
"iuphar": "objectId:2822",
"location": "11p15.5",
"location_sortable": "11p15.5",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_506|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_506.xml"
],
"mane_select": [
"ENST00000311189.8",
"NM_005343.4"
],
"mgd_id": [
"MGI:96224"
],
"name": "HRas proto-oncogene, GTPase",
"omim_id": [
"190020"
],
"orphanet": 122499,
"prev_name": [
"v-Ha-ras Harvey rat sarcoma viral oncogene homolog",
"Harvey rat sarcoma viral oncogene homolog"
],
"prev_symbol": [
"HRAS1"
],
"refseq_accession": [
"NM_176795"
],
"rgd_id": [
"RGD:2827"
],
"status": "Approved",
"symbol": "HRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc010qvx.3",
"uniprot_ids": [
"P01112"
],
"uuid": "5e0f7545-006b-46cf-b1dd-1b96b73c88d3",
"vega_id": "OTTHUMG00000131919"
},
"NCBI": {
"id": "3265"
}
},
"entId": "HRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5173",
"entType": "Gene",
"ldhId": "135641819",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641819",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056950878109700,
"agr": "HGNC:6407",
"alias_symbol": [
"KRAS1",
"K-Ras4B"
],
"ccds_id": [
"CCDS8703",
"CCDS8702"
],
"cosmic": "KRAS",
"date_approved_reserved": "1988-06-02",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-10",
"date_symbol_changed": "2005-01-24",
"ena": [
"BC010502"
],
"ensembl_gene_id": "ENSG00000133703",
"entrez_id": "3845",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:6407",
"iuphar": "objectId:2824",
"location": "12p12.1",
"location_sortable": "12p12.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_344|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_344.xml"
],
"mane_select": [
"ENST00000311936.8",
"NM_004985.5"
],
"mgd_id": [
"MGI:96680"
],
"name": "KRAS proto-oncogene, GTPase",
"omim_id": [
"190070"
],
"orphanet": 122879,
"prev_name": [
"v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog",
"v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog",
"Kirsten rat sarcoma viral oncogene homolog"
],
"prev_symbol": [
"KRAS2"
],
"refseq_accession": [
"NM_033360"
],
"rgd_id": [
"RGD:2981"
],
"status": "Approved",
"symbol": "KRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001rgp.3",
"uniprot_ids": [
"P01116"
],
"uuid": "b433a2e9-c3eb-451d-a0cd-0c88f1d6935f",
"vega_id": "OTTHUMG00000171193"
},
"NCBI": {
"id": "3845"
}
},
"entId": "KRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6407",
"entType": "Gene",
"ldhId": "135641817",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641817",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056958617649200,
"agr": "HGNC:9644",
"alias_name": [
"SH2 domain-containing protein tyrosine phosphatase 2"
],
"alias_symbol": [
"BPTP3",
"SH-PTP2",
"SHP-2",
"PTP2C",
"SHP2"
],
"ccds_id": [
"CCDS9163",
"CCDS81741",
"CCDS58280"
],
"cosmic": "PTPN11",
"date_approved_reserved": "1993-03-03",
"date_modified": "2021-05-26",
"date_name_changed": "2019-02-14",
"ena": [
"D13540"
],
"ensembl_gene_id": "ENSG00000179295",
"entrez_id": "5781",
"gene_group": [
"SH2 domain containing",
"Protein tyrosine phosphatases non-receptor type"
],
"gene_group_id": [
741,
812
],
"hgnc_id": "HGNC:9644",
"location": "12q24.13",
"location_sortable": "12q24.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_614|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_614.xml"
],
"mane_select": [
"ENST00000351677.7",
"NM_002834.5"
],
"mgd_id": [
"MGI:99511"
],
"name": "protein tyrosine phosphatase non-receptor type 11",
"omim_id": [
"176876"
],
"orphanet": 118143,
"prev_name": [
"Noonan syndrome 1",
"protein tyrosine phosphatase, non-receptor type 11"
],
"prev_symbol": [
"NS1"
],
"pubmed_id": [
7894486,
1280823
],
"refseq_accession": [
"NM_001330437"
],
"rgd_id": [
"RGD:3447"
],
"status": "Approved",
"symbol": "PTPN11",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001ttx.4",
"uniprot_ids": [
"Q06124"
],
"uuid": "3598f5ec-29fc-495b-a74a-9a05a111ab30",
"vega_id": "OTTHUMG00000134334"
},
"NCBI": {
"id": "5781"
}
},
"entId": "PTPN11",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9644",
"entType": "Gene",
"ldhId": "135641816",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641816",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---F"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056959328583700,
"agr": "HGNC:10023",
"alias_name": [
"Ric-like, expressed in many tissues",
"GTP-binding protein Roc1"
],
"alias_symbol": [
"RIBB",
"ROC1",
"MGC125864",
"MGC125865"
],
"ccds_id": [
"CCDS58037",
"CCDS1123",
"CCDS58036"
],
"date_approved_reserved": "1996-08-28",
"date_modified": "2021-04-13",
"date_name_changed": "2016-05-04",
"date_symbol_changed": "2002-09-13",
"ena": [
"AF084462"
],
"ensembl_gene_id": "ENSG00000143622",
"entrez_id": "6016",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:10023",
"location": "1q22",
"location_sortable": "01q22",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1372|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1372.xml"
],
"mane_select": [
"ENST00000368323.8",
"NM_006912.6"
],
"mgd_id": [
"MGI:108053"
],
"name": "Ras like without CAAX 1",
"omim_id": [
"609591"
],
"orphanet": 358630,
"prev_name": [
"Ric (Drosophila)-like, expressed in many tissues"
],
"prev_symbol": [
"RIT"
],
"pubmed_id": [
8824319,
8918462
],
"refseq_accession": [
"NM_006912"
],
"rgd_id": [
"RGD:1559874"
],
"status": "Approved",
"symbol": "RIT1",
"ucsc_id": "uc001fmh.3",
"uniprot_ids": [
"Q92963"
],
"uuid": "43b6b6f9-9c5d-4df6-ba5e-a347f30ab080",
"vega_id": "OTTHUMG00000014104"
},
"NCBI": {
"id": "6016"
}
},
"entId": "RIT1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10023",
"entType": "Gene",
"ldhId": "135641820",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641820",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--E"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056958857773000,
"agr": "HGNC:9829",
"alias_name": [
"C-Raf proto-oncogene, serine/threonine kinase"
],
"alias_symbol": [
"Raf-1",
"c-Raf",
"CRAF"
],
"ccds_id": [
"CCDS87047",
"CCDS2612"
],
"cosmic": "RAF1",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-04-13",
"date_name_changed": "2014-06-26",
"ena": [
"X03484"
],
"ensembl_gene_id": "ENSG00000132155",
"entrez_id": "5894",
"gene_group": [
"Mitogen-activated protein kinase kinase kinases",
"RAF family"
],
"gene_group_id": [
654,
1157
],
"hgnc_id": "HGNC:9829",
"iuphar": "objectId:2184",
"location": "3p25.2",
"location_sortable": "03p25.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_413|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_413.xml"
],
"mane_select": [
"ENST00000442415.7",
"NM_001354689.3"
],
"mgd_id": [
"MGI:97847"
],
"name": "Raf-1 proto-oncogene, serine/threonine kinase",
"omim_id": [
"164760"
],
"orphanet": 138722,
"prev_name": [
"v-raf-1 murine leukemia viral oncogene homolog 1"
],
"pubmed_id": [
1611909
],
"refseq_accession": [
"NM_002880"
],
"rgd_id": [
"RGD:3531"
],
"status": "Approved",
"symbol": "RAF1",
"ucsc_id": "uc003bxf.5",
"uniprot_ids": [
"P04049"
],
"uuid": "b38560c9-a1b1-4bbd-a005-376c7eaca0b3",
"vega_id": "OTTHUMG00000129789"
},
"NCBI": {
"id": "5894"
}
},
"entId": "RAF1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9829",
"entType": "Gene",
"ldhId": "135641813",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641813",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--D"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056955918614500,
"agr": "HGNC:7989",
"alias_symbol": [
"N-ras"
],
"ccds_id": [
"CCDS877"
],
"cosmic": "NRAS",
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2017-02-27",
"ena": [
"BC005219"
],
"ensembl_gene_id": "ENSG00000213281",
"entrez_id": "4893",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:7989",
"iuphar": "objectId:2823",
"location": "1p13.2",
"location_sortable": "01p13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"NRASbase: Mutation registry for autoimmune lymphoproliferative syndrome type IV|http://structure.bmc.lu.se/idbase/NRASbase/",
"LRG_92|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_92.xml"
],
"mane_select": [
"ENST00000369535.5",
"NM_002524.5"
],
"mgd_id": [
"MGI:97376"
],
"name": "NRAS proto-oncogene, GTPase",
"omim_id": [
"164790"
],
"orphanet": 221346,
"prev_name": [
"neuroblastoma RAS viral (v-ras) oncogene homolog",
"neuroblastoma RAS viral oncogene homolog"
],
"pubmed_id": [
6705568,
11524732
],
"refseq_accession": [
"NM_002524"
],
"rgd_id": [
"RGD:3205"
],
"status": "Approved",
"symbol": "NRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc009wgu.4",
"uniprot_ids": [
"P01111"
],
"uuid": "50dccc85-0457-43d2-8c89-b4014ec96185",
"vega_id": "OTTHUMG00000012059"
},
"NCBI": {
"id": "4893"
}
},
"entId": "NRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7989",
"entType": "Gene",
"ldhId": "135641812",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641812",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---D"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056962873819100,
"agr": "HGNC:15454",
"alias_symbol": [
"KIAA0862",
"SOC2",
"SUR-8",
"SOC-2",
"SUR8"
],
"ccds_id": [
"CCDS7568",
"CCDS58095"
],
"date_approved_reserved": "2001-03-30",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ena": [
"AB020669"
],
"ensembl_gene_id": "ENSG00000108061",
"entrez_id": "8036",
"gene_group": [
"MicroRNA protein coding host genes"
],
"gene_group_id": [
1691
],
"hgnc_id": "HGNC:15454",
"location": "10q25.2",
"location_sortable": "10q25.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_753|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_753.xml"
],
"mane_select": [
"ENST00000369452.9",
"NM_007373.4"
],
"mgd_id": [
"MGI:1927197"
],
"name": "SHOC2 leucine rich repeat scaffold protein",
"omim_id": [
"602775"
],
"orphanet": 220877,
"prev_name": [
"soc-2 (suppressor of clear, C.elegans) homolog",
"soc-2 suppressor of clear homolog (C. elegans)",
"SHOC2 leucine-rich repeat scaffold protein",
"SHOC2, leucine rich repeat scaffold protein"
],
"pubmed_id": [
9618511,
9674433,
10783161
],
"refseq_accession": [
"NM_007373"
],
"rgd_id": [
"RGD:1308146"
],
"status": "Approved",
"symbol": "SHOC2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001kzl.5",
"uniprot_ids": [
"Q9UQ13"
],
"uuid": "9ee464ec-a210-4c21-9ac1-10b8023c489b",
"vega_id": "OTTHUMG00000019047"
},
"NCBI": {
"id": "8036"
}
},
"entId": "SHOC2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:15454",
"entType": "Gene",
"ldhId": "135641811",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641811",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--G"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056952808538000,
"agr": "HGNC:6842",
"alias_symbol": [
"MEK2"
],
"ccds_id": [
"CCDS12120"
],
"cosmic": "MAP2K2",
"date_approved_reserved": "1993-11-05",
"date_modified": "2021-04-13",
"ena": [
"L11285"
],
"ensembl_gene_id": "ENSG00000126934",
"entrez_id": "5605",
"enzyme_id": [
"2.7.12.2"
],
"gene_group": [
"Mitogen-activated protein kinase kinases"
],
"gene_group_id": [
653
],
"hgnc_id": "HGNC:6842",
"iuphar": "objectId:2063",
"location": "19p13.3",
"location_sortable": "19p13.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_750|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_750.xml"
],
"mane_select": [
"ENST00000262948.10",
"NM_030662.4"
],
"mgd_id": [
"MGI:1346867"
],
"name": "mitogen-activated protein kinase kinase 2",
"omim_id": [
"601263"
],
"orphanet": 123140,
"prev_symbol": [
"PRKMK2"
],
"pubmed_id": [
8388392
],
"refseq_accession": [
"NM_030662"
],
"rgd_id": [
"RGD:61888"
],
"status": "Approved",
"symbol": "MAP2K2",
"ucsc_id": "uc002lzk.4",
"uniprot_ids": [
"P36507"
],
"uuid": "52a104b3-3f62-4cb6-ad59-1fe0fbb432f2",
"vega_id": "OTTHUMG00000134286"
},
"NCBI": {
"id": "5605"
}
},
"entId": "MAP2K2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6842",
"entType": "Gene",
"ldhId": "135641821",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641821",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC---"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963944415200,
"agr": "HGNC:11187",
"alias_symbol": [
"HGF",
"GF1"
],
"ccds_id": [
"CCDS1802"
],
"curator_notes": [
"There is no relationship between this gene and the plant ‘salt overly sensitive’ gene with the same symbol."
],
"date_approved_reserved": "1993-10-27",
"date_modified": "2021-04-13",
"date_name_changed": "2015-11-10",
"ena": [
"L13857"
],
"ensembl_gene_id": "ENSG00000115904",
"entrez_id": "6654",
"gene_group": [
"Pleckstrin homology domain containing",
"Dbl family Rho GEFs"
],
"gene_group_id": [
682,
722
],
"hgnc_id": "HGNC:11187",
"iuphar": "objectId:3096",
"location": "2p22.1",
"location_sortable": "02p22.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_754|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_754.xml"
],
"mane_select": [
"ENST00000402219.8",
"NM_005633.4"
],
"mgd_id": [
"MGI:98354"
],
"name": "SOS Ras/Rac guanine nucleotide exchange factor 1",
"omim_id": [
"182530"
],
"orphanet": 119781,
"prev_name": [
"gingival fibromatosis, hereditary, 1",
"son of sevenless homolog 1 (Drosophila)"
],
"prev_symbol": [
"GINGF"
],
"pubmed_id": [
8276400,
10995566
],
"refseq_accession": [
"NM_005633"
],
"rgd_id": [
"RGD:1310949"
],
"status": "Approved",
"symbol": "SOS1",
"ucsc_id": "uc061ikm.1",
"uniprot_ids": [
"Q07889"
],
"uuid": "403c9348-75fb-4105-b6ef-45a6bb741b36",
"vega_id": "OTTHUMG00000102109"
},
"NCBI": {
"id": "6654"
}
},
"entId": "SOS1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11187",
"entType": "Gene",
"ldhId": "135641814",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641814",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---G"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056943387082800,
"agr": "HGNC:1097",
"alias_symbol": [
"BRAF1"
],
"ccds_id": [
"CCDS87555",
"CCDS5863"
],
"cosmic": "BRAF",
"date_approved_reserved": "1991-07-16",
"date_modified": "2021-05-26",
"date_name_changed": "2014-06-26",
"ena": [
"M95712"
],
"ensembl_gene_id": "ENSG00000157764",
"entrez_id": "673",
"gene_group": [
"Mitogen-activated protein kinase kinase kinases",
"RAF family"
],
"gene_group_id": [
654,
1157
],
"hgnc_id": "HGNC:1097",
"iuphar": "objectId:1943",
"location": "7q34",
"location_sortable": "07q34",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_299|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_299.xml"
],
"mane_select": [
"ENST00000644969.2",
"NM_001374258.1"
],
"mgd_id": [
"MGI:88190"
],
"name": "B-Raf proto-oncogene, serine/threonine kinase",
"omim_id": [
"164757"
],
"orphanet": 119066,
"prev_name": [
"v-raf murine sarcoma viral oncogene homolog B"
],
"pubmed_id": [
2284096,
1565476
],
"refseq_accession": [
"NM_004333"
],
"rgd_id": [
"RGD:619908"
],
"status": "Approved",
"symbol": "BRAF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003vwc.5",
"uniprot_ids": [
"P15056"
],
"uuid": "572c5ff2-c510-496c-a055-0342aaa6d9eb",
"vega_id": "OTTHUMG00000157457"
},
"NCBI": {
"id": "673"
}
},
"entId": "BRAF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1097",
"entType": "Gene",
"ldhId": "135641822",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641822",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyAy---"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056952807489500,
"agr": "HGNC:6840",
"alias_symbol": [
"MEK1",
"MAPKK1"
],
"ccds_id": [
"CCDS10216"
],
"cosmic": "MAP2K1",
"date_approved_reserved": "1993-11-05",
"date_modified": "2021-04-13",
"ena": [
"L11284"
],
"ensembl_gene_id": "ENSG00000169032",
"entrez_id": "5604",
"enzyme_id": [
"2.7.12.2"
],
"gene_group": [
"Mitogen-activated protein kinase kinases"
],
"gene_group_id": [
653
],
"hgnc_id": "HGNC:6840",
"iuphar": "objectId:2062",
"location": "15q22.31",
"location_sortable": "15q22.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"The Globin Gene Server|http://lovd.bx.psu.edu/home.php?select_db=MAP2K1",
"LRG_725|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_725.xml"
],
"mane_select": [
"ENST00000307102.10",
"NM_002755.4"
],
"mgd_id": [
"MGI:1346866"
],
"name": "mitogen-activated protein kinase kinase 1",
"omim_id": [
"176872"
],
"orphanet": 123135,
"prev_symbol": [
"PRKMK1"
],
"pubmed_id": [
9465908,
8388392
],
"refseq_accession": [
"NM_002755"
],
"rgd_id": [
"RGD:70495"
],
"status": "Approved",
"symbol": "MAP2K1",
"ucsc_id": "uc010bhq.4",
"uniprot_ids": [
"Q02750"
],
"uuid": "dbe1a6fc-0d4c-48a2-9a8f-b66f89a4bd4e",
"vega_id": "OTTHUMG00000133196"
},
"NCBI": {
"id": "5604"
}
},
"entId": "MAP2K1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6840",
"entType": "Gene",
"ldhId": "135641818",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641818",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963946512400,
"agr": "HGNC:11188",
"ccds_id": [
"CCDS9697"
],
"curator_notes": [
"There is no relationship between this gene and the plant ‘salt overly sensitive’ gene with the same symbol."
],
"date_approved_reserved": "1993-10-27",
"date_modified": "2016-10-05",
"date_name_changed": "2015-11-10",
"ena": [
"L13858"
],
"ensembl_gene_id": "ENSG00000100485",
"entrez_id": "6655",
"gene_group": [
"Pleckstrin homology domain containing",
"Dbl family Rho GEFs"
],
"gene_group_id": [
682,
722
],
"hgnc_id": "HGNC:11188",
"location": "14q21.3",
"location_sortable": "14q21.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000216373.10",
"NM_006939.4"
],
"mgd_id": [
"MGI:98355"
],
"name": "SOS Ras/Rho guanine nucleotide exchange factor 2",
"omim_id": [
"601247"
],
"orphanet": 434401,
"prev_name": [
"son of sevenless (Drosophilia) homolog 2",
"son of sevenless homolog 2 (Drosophila)"
],
"pubmed_id": [
8276400
],
"refseq_accession": [
"NM_006939"
],
"rgd_id": [
"RGD:620435"
],
"status": "Approved",
"symbol": "SOS2",
"ucsc_id": "uc001wxs.5",
"uniprot_ids": [
"Q07890"
],
"uuid": "00e6fd97-e609-4db9-8c21-ad4c9da431c6",
"vega_id": "OTTHUMG00000140292"
},
"NCBI": {
"id": "6655"
}
},
"entId": "SOS2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11188",
"entType": "Gene",
"ldhId": "135641815",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641815",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "004_nuclear_BRAF_HRAS_KRAS_MAP2K1_MAP2K2_NRAS_PTPN11_RAF1_RIT1_SHOC2_SOS1_SOS2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0054637"
]
}
],
"gene": "SHOC2"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060"
]
}
],
"gene": "NRAS"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0018997"
]
}
],
"gene": "RAF1"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0018997"
]
}
],
"gene": "SOS1"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0018997"
]
}
],
"gene": "SOS2"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0007893",
"MONDO:0018997"
]
}
],
"gene": "PTPN11"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0015280",
"MONDO:0018997"
]
}
],
"gene": "KRAS"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0015280"
]
}
],
"gene": "MAP2K1"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0009026"
]
}
],
"gene": "HRAS"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060"
]
}
],
"gene": "RIT1"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0015280"
]
}
],
"gene": "MAP2K2"
},
{
"diseases": [
{
"recommendedMondoIds": [
"MONDO:0021060",
"MONDO:0015280"
]
}
],
"gene": "BRAF"
}
],
"ns": "004"
},
"entType": "RuleSet",
"ldhId": "135640573",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640573",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN047",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:16.731Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:29:35.249Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:27:46.530Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:43.388Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"047"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN047",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243117",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243117",
"modified": "2023-09-06T21:12:43.520Z",
"modifier": "sharriso",
"rev": "_h6SHykS--J"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN038",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:41.717Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:17:40.158Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:16:53.504Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:10.967Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"038"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN038",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243108",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243108",
"modified": "2023-09-06T21:11:11.189Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--H"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN043",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:01.042Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:41:50.919Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:39:57.331Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:09.143Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"043"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN043",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243113",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243113",
"modified": "2023-09-06T21:12:09.271Z",
"modifier": "sharriso",
"rev": "_h6SHykG--E"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN041",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:53.367Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:35:43.611Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:34:23.894Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:50.393Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"041"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN041",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243111",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243111",
"modified": "2023-09-06T21:11:50.611Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN048",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:20.429Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:50:54.076Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:49:40.294Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:53.839Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"048"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN048",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243118",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243118",
"modified": "2023-09-06T21:12:53.963Z",
"modifier": "sharriso",
"rev": "_h6SHykG--T"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN042",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:57.208Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:38:42.348Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:37:09.802Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:00.498Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"042"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN042",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243112",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243112",
"modified": "2023-09-06T21:12:00.626Z",
"modifier": "sharriso",
"rev": "_h6SHykG--S"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN040",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:49.407Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:33:42.890Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:31:56.497Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:39.602Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"040"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN040",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243110",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243110",
"modified": "2023-09-06T21:11:39.749Z",
"modifier": "sharriso",
"rev": "_h6SHykS--G"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN049",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:24.322Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:18:54.826Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:18:12.960Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:05.564Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"049"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN049",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243119",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243119",
"modified": "2023-09-06T21:13:05.701Z",
"modifier": "sharriso",
"rev": "_h6SHykS--K"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN046",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:12.804Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:27:14.680Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:25:24.102Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:35.383Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"046"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN046",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243116",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243116",
"modified": "2023-09-06T21:12:35.517Z",
"modifier": "sharriso",
"rev": "_h6SHykS--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN045",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:08.948Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:49:05.328Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:47:46.078Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:27.247Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"045"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN045",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243115",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243115",
"modified": "2023-09-06T21:12:27.379Z",
"modifier": "sharriso",
"rev": "_h6SHykG--F"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN044",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:04.995Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:47:09.101Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:45:31.721Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:17.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"044"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN044",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243114",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243114",
"modified": "2023-09-06T21:12:18.143Z",
"modifier": "sharriso",
"rev": "_h6SHykS--H"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN039",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:45.478Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:16:28.104Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:15:00.296Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:27.125Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"039"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN039",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243109",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243109",
"modified": "2023-09-06T21:11:27.252Z",
"modifier": "sharriso",
"rev": "_h6SHykG--D"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "005_PP3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "005",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN.\n * For missense variants, award PP3 if REVEL score is ≥0.7.\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3.\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638903",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638903",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--F"
},
{
"entContent": {
"_uniqueProp": "005_BP5_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "005",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant in an autosomal dominant gene found in a patient with an alternate explanation.\n* Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.\n* Autosomal dominant: Can use BP5 as outlined by Richards 2015.\n\n * Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638900",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638900",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxou---"
},
{
"entContent": {
"_uniqueProp": "005_PS4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "005",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR\nAutosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Autosomal dominant: ≥6 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Autosomal dominant: ≥2 probands with variant, and variant meets PM2_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638898",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638898",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--J"
},
{
"entContent": {
"_uniqueProp": "005_BP6_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "005",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432874",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432874",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--_"
},
{
"entContent": {
"_uniqueProp": "005_BA1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "005",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638901",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638901",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--L"
},
{
"entContent": {
"_uniqueProp": "005_BP4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "005",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638896",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG---"
},
{
"entContent": {
"_uniqueProp": "005_PS3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "005",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Knock-in mouse model demonstrates the phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate\n* Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to\nboth a negative control (or H2O injected control) and a wildtype-transfected cell. PS3_Moderate\nwould be applied if the variant results in no dye transfer or significantly different dye transfer when\ncompared to the wildtype.\n* Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "SLC26A4: Radio isotope and fluorescence assays → PS3_Supporting\n* Radio Isotope Assays: PS3_Supporting would be applied when cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin.\n* Fluorescence Assays: PS3_Supporting would be applied when a cell transfected with the mutant SLC26A4 shows a statistically significant difference in fluorescence (ΔFmax %) compared to the wildtype protein, and when the fluorescence is not significantly different from that of an empty vector control.\nCOCH: Localization, secretion, and dimerization studies performed using immunofluorescence and\nWestern blotting techniques →PS3_Supporting\n* Localization: PS3_Supporting would be applied if the mutant cochlin protein does not aggregate into extracellular deposits or in the perinuclear region, comparable to the localization of wildtype cochlin.\n* Secretion: PS3_Supporting would be applied if cochlin protein containing the variant does not show secretion from transfected cells, but aggregates in cell regions such as the ER, Golgi and nucleus or is degraded.\n* Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. PS3_Supporting would be applied if the cochlin protein containing the variant forms more, or less, stable disulfide bonds when compared to the wildtype in non-reducing conditions.\n* If not listed above, OK to use PS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND \n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638895",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--W"
},
{
"entContent": {
"_uniqueProp": "005_BP3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "005",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame indels in repeat region without known function.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638894",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638894",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--M"
},
{
"entContent": {
"_uniqueProp": "005_BS4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "005",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset).\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound).\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Sex -based differences (infertility, genes on X chromosomes)\n * Audiogram shape.\n * May not be completely consistent among family members even with same etiology.\n* Genotype+/phenotype-\n * Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc.\n * If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n * Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss).\n * Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n * Any evidence for reduced penetrance, do not use BS4",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638889",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638889",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--E"
},
{
"entContent": {
"_uniqueProp": "005_PM4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "005",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\n* No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638885",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638885",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--B"
},
{
"entContent": {
"_uniqueProp": "005_BS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "005",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0086",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638882",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638882",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--e"
},
{
"entContent": {
"_uniqueProp": "005_PP5_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "005",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432875",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432875",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--K"
},
{
"entContent": {
"_uniqueProp": "005_PM2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "005",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).\n* Background: Rarity or absence in the general population is not robust evidence for pathogenicity, particularly for autosomal recessive disorders. However, the ACMG/AMP Guidelines were devised in such a way that absence or rarity were considered moderate evidence towards pathogenicity, and the framework requires multiple pieces of evidence to classify a variant as likely pathogenic or pathogenic.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638907",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638907",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--X"
},
{
"entContent": {
"_uniqueProp": "005_PM1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "005",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region).\n* KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; https://www.uniprot.org/uniprot/P56696). There are only two missense variants in this region in gnomAD, each with only single allele (http://gnomad.broadinstitute.org/; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638906",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638906",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--E"
},
{
"entContent": {
"_uniqueProp": "005_PP4_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "005",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638905",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--d"
},
{
"entContent": {
"_uniqueProp": "005_BP7_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "005",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant with no predicted impact to splicing.\nNo changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638904",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--_"
},
{
"entContent": {
"_uniqueProp": "005_PP2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "005",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638902",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638902",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--c"
},
{
"entContent": {
"_uniqueProp": "005_PS2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "005",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638893",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638893",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--I"
},
{
"entContent": {
"_uniqueProp": "005_BP2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "005",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\nUse with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638892",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638892",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--F"
},
{
"entContent": {
"_uniqueProp": "005_PM6_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "005",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638890",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638890",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--a"
},
{
"entContent": {
"_uniqueProp": "005_BP1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "005",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638888",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638888",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--F"
},
{
"entContent": {
"_uniqueProp": "005_BS3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "005",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Functional study shows no deleterious effect (predefined list).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n* Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached):\n * GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting\n * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype.\n * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype.\n * SLC26A4: Radio isotope and fluorescence assays → BS3_Supporting\n * Radio Isotope Assays: BS3_Supporting would be applied if the variant results in iodide efflux levels comparable to the wildtype.\n * Fluorescence assay: BS3_Supporting would be applied if the variant results in fluorescence comparable to the wildtype\n * COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and Western blotting techniques → BS3_Supporting\n * Localization: BS3_Supporting would be applied if the variant results in extracellular deposits comparable to the wildtype.\n * Secretion: BS3_Supporting would be applied if the variant results in secretion comparable to the wildtype.\n * Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. BS3_Supporting would be applied if the variant results in molecular weight and size comparable to the wildtype.\n* If not listed above, OK to use BS3_Supporting for other genes/functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638886",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638886",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--D"
},
{
"entContent": {
"_uniqueProp": "005_PM3_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "005",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0038",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points awarded from tables 7a and 7b\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0058",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points awarded from tables 7a and 7b\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point awarded from tables 7a and 7b.\nExample: Detected in trans with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0027",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points awarded from tables 7a and 7b\nExamples: Two variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638883",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638883",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--Y"
},
{
"entContent": {
"_uniqueProp": "005_PVS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "005",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.\n* PVS1 should also be considered for the following genes with variants assessed in the Hearing Loss Variant Pilot: GJB2, CDH23, USH2A, SLC26A4, MYO6, MYO7A, TECTA, KCNQ4.\n* For other genes, LOF must be an established disease mechanism, and the gene/disease association must be Strong or Definitive clinical validity level as outlined in Strande et al. 2017 (PMID: 28552198).\n* If above criteria is met, follow PVS1 flowchart as recommended by the SVI.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "001",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638899",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638899",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--H"
},
{
"entContent": {
"_uniqueProp": "005_PP1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "005",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregation in three affected relatives for recessive and five affected relatives for dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in two affected relatives for recessive and 4 affected relatives for dominant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in one affected relative for recessive and two affected relatives for dominant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638897",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--b"
},
{
"entContent": {
"_uniqueProp": "005_PS1_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "005",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as an established pathogenic variant; OR\nsplice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications\n * Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638891",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638891",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--A"
},
{
"entContent": {
"_uniqueProp": "005_PM5_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "005",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0056",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at same codon as two different pathogenic missense variants.\n* Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data)\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638887",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638887",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--Z"
},
{
"entContent": {
"_uniqueProp": "005_BS2_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH23",
"COCH",
"GJB2",
"KCNQ4",
"MYO6",
"MYO7A",
"SLC26A4",
"TECTA",
"USH2A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "005",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638884",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638884",
"modified": "2022-05-23T18:09:58.022Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--C"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/CN043648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#disease_grouping"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
}
],
"xrefs": [
{
"val": "EFO:0009076"
},
{
"val": "DOID:0050563"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:CN043648"
},
{
"val": "GARD:0006410"
},
{
"val": "MESH:C580334"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642106",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642106",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdm--_"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/CN043648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#disease_grouping"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
}
],
"xrefs": [
{
"val": "EFO:0009076"
},
{
"val": "DOID:0050563"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:CN043648"
},
{
"val": "GARD:0006410"
},
{
"val": "MESH:C580334"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642104",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642104",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdm---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016484",
"lbl": "Usher syndrome type 2",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016484"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome_type_2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/33632175"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/83288"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/232058008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0339534"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0110827"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C126328"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_231178"
}
],
"definition": {
"val": "A syndrome characterized by congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies, no abnormalities in the vestibular system, and retinitis pigmentosa.",
"xrefs": [
"NCIT:C126328"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH2",
"xrefs": [
"DOID:0110827",
"Orphanet:231178"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome type 2",
"xrefs": [
"DOID:0110827",
"NCIT:C126328",
"Orphanet:231178",
"icd11.foundation:33632175"
]
}
],
"xrefs": [
{
"val": "DOID:0110827"
},
{
"val": "GARD:5440"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:83288"
},
{
"val": "NANDO:1200943"
},
{
"val": "NCIT:C126328"
},
{
"val": "Orphanet:231178"
},
{
"val": "SCTID:232058008"
},
{
"val": "UMLS:C0339534"
},
{
"val": "icd11.foundation:33632175"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016484",
"name": "Usher syndrome type 2",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0016484",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016484",
"entType": "Disease",
"ldhId": "135642103",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642103",
"modified": "2025-10-07T15:45:51.651Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xr2W---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/CN043648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#disease_grouping"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
}
],
"xrefs": [
{
"val": "EFO:0009076"
},
{
"val": "DOID:0050563"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:CN043648"
},
{
"val": "GARD:0006410"
},
{
"val": "MESH:C580334"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642108",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642108",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdi--l"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_genetic_deafness"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness"
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness"
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness"
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness"
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642105",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642105",
"modified": "2025-10-07T15:46:46.842Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Yhd----"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010169",
"lbl": "Usher syndrome type 2A",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome_type_iia"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/338513"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C536490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1848634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0110838"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/276901"
}
],
"definition": {
"val": "Any Usher syndrome in which the cause of the disease is a mutation in the USH2A gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH2A",
"xrefs": [
"DOID:0110838",
"MONDO:Lexical",
"OMIM:276901"
]
},
{
"pred": "hasExactSynonym",
"val": "USH2A Usher syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome caused by mutation in USH2A",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome type 2A",
"xrefs": [
"DOID:0110838"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome type IIA",
"xrefs": [
"DOID:0110838"
]
},
{
"pred": "hasExactSynonym",
"val": "retinal disease in usher syndrome type IIA, modifier of"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "US2",
"xrefs": [
"GARD:0005440"
]
},
{
"pred": "hasRelatedSynonym",
"val": "USHER syndrome, type IIA",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Usher syndrome, type 2A"
}
],
"xrefs": [
{
"val": "DOID:0110838"
},
{
"val": "GARD:15241"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:338513"
},
{
"val": "MESH:C536490"
},
{
"val": "OMIM:276901"
},
{
"val": "UMLS:C1848634"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010169",
"name": "Usher syndrome type 2A",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0010169",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010169",
"entType": "Disease",
"ldhId": "135642101",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642101",
"modified": "2025-10-07T15:44:07.088Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WFqu---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010134",
"lbl": "Pendred syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6878"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010134"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/pendred_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1156056623"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/82890"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C536648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/70348004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271829"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060744"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C121745"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_705"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/274600"
}
],
"definition": {
"val": "Pendred syndrome (PDS) is a clinically variable genetic disorder characterized by bilateral sensorineural hearing loss and euthyroid goiter.",
"xrefs": [
"Orphanet:705"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Pendred syndrome",
"xrefs": [
"DOID:0060744",
"MONDO:Lexical",
"NCIT:C121745",
"OMIM:274600",
"Orphanet:705",
"icd11.foundation:1156056623"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "TDH2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital hypothyroidism due to dyshormonogenesis 2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "deafness with goiter",
"xrefs": [
"DOID:0060744",
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "deafness with goitre"
},
{
"pred": "hasExactSynonym",
"val": "genetic defect in thyroid hormonogenesis 2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "goiter-deafness syndrome",
"xrefs": [
"DOID:0060744",
"OMIM:274600",
"Orphanet:705"
]
},
{
"pred": "hasExactSynonym",
"val": "hypothyroidism, congenital, due to dyshormonogenesis, 2B",
"xrefs": [
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"val": "thyroid dyshormonogenesis 2B",
"xrefs": [
"DOID:0060744",
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"val": "thyroid hormonogenesis, genetic defect in, 2B",
"xrefs": [
"OMIM:274600"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "autosomal recessive sensorineural hearing impairment and goiter",
"xrefs": [
"GARD:0004271"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "autosomal recessive sensorineural hearing impairment and goitre"
}
],
"xrefs": [
{
"val": "DOID:0060744"
},
{
"val": "GARD:4271"
},
{
"val": "MEDGEN:82890"
},
{
"val": "MESH:C536648"
},
{
"val": "NCIT:C121745"
},
{
"val": "NORD:2030"
},
{
"val": "OMIM:274600"
},
{
"val": "Orphanet:705"
},
{
"val": "SCTID:70348004"
},
{
"val": "UMLS:C0271829"
},
{
"val": "icd11.foundation:1156056623"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010134",
"name": "Pendred syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0010134",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010134",
"entType": "Disease",
"ldhId": "135642098",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642098",
"modified": "2025-10-07T15:44:07.088Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WFiS---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010984",
"lbl": "Usher syndrome type 1D",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome_type_id"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/5438/usher-syndrome-type-1d"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/322051"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1832845"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0110831"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/601067"
}
],
"definition": {
"val": "A form of Usher syndrome type I that is caused by homozygous or compound heterozygous mutation in the gene encoding cadherin-23 (CDH23) on chromosome 10q22. It is inherited in an autosomal recessive manner.",
"xrefs": [
"OMIM:601067"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH1D",
"xrefs": [
"DOID:0110831",
"MONDO:Lexical",
"OMIM:601067"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome type 1D",
"xrefs": [
"DOID:0110831"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome type ID",
"xrefs": [
"DOID:0110831"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher syndrome, type 1D/F digenic"
},
{
"pred": "hasRelatedSynonym",
"val": "USHER syndrome, type ID",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ush1D/F, Cdh23/Pcdh15, digenic"
},
{
"pred": "hasRelatedSynonym",
"val": "Usher syndrome, type 1D",
"xrefs": [
"GARD:0005438"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Usher syndrome, type Id/F, Cdh23/Pcdh15, digenic"
}
],
"xrefs": [
{
"val": "DOID:0110831"
},
{
"val": "GARD:5438"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:322051"
},
{
"val": "OMIM:601067"
},
{
"val": "UMLS:C1832845"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010984",
"name": "Usher syndrome type 1D",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0010984",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010984",
"entType": "Disease",
"ldhId": "135642110",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642110",
"modified": "2025-10-07T15:44:20.433Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WSwC---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
}
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_disease"
],
"synonyms": [
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush",
"xrefs": [
"Orphanet:886"
]
}
],
"xrefs": [
{
"val": "Orphanet:886"
},
{
"val": "NCIT:C85217"
},
{
"val": "DOID:0050439"
},
{
"val": "OMIMPS:276900"
},
{
"val": "MedDRA:10063396"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MESH:D052245"
},
{
"val": "GARD:0007843"
},
{
"val": "UMLS:C0271097"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642102",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642102",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdi--m"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005365",
"lbl": "hearing loss disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005365"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/235586"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D034381"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/15188001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1384666"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/H90"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C35731"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0004238"
}
],
"definition": {
"val": "A partial or complete loss of hearing in one or both ears. It is classified as conductive, sensory, or central.",
"xrefs": [
"NCIT:C35731"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hearing loss",
"xrefs": [
"NCIT:C35731"
]
},
{
"pred": "hasExactSynonym",
"val": "hypoacuses",
"xrefs": [
"MESH:D034381"
]
},
{
"pred": "hasExactSynonym",
"val": "hypoacusis",
"xrefs": [
"MESH:D034381"
]
},
{
"pred": "hasExactSynonym",
"val": "loss of hearing"
},
{
"pred": "hasExactSynonym",
"val": "loss, hearing",
"xrefs": [
"MESH:D034381"
]
},
{
"pred": "hasNarrowSynonym",
"val": "deafness",
"xrefs": [
"https://orcid.org/0000-0002-6601-2165"
]
},
{
"pred": "hasRelatedSynonym",
"val": "hearing impairment",
"xrefs": [
"MESH:D034381"
]
}
],
"xrefs": [
{
"val": "EFO:0004238"
},
{
"val": "ICD10CM:H90"
},
{
"val": "ICD9:389"
},
{
"val": "ICD9:389.8"
},
{
"val": "ICD9:389.9"
},
{
"val": "MEDGEN:235586"
},
{
"val": "MESH:D034381"
},
{
"val": "NCIT:C35731"
},
{
"val": "SCTID:15188001"
},
{
"val": "UMLS:C1384666"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005365",
"name": "hearing loss disorder",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005365",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005365",
"entType": "Disease",
"ldhId": "135642096",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642096",
"modified": "2025-10-07T15:42:58.404Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7VCkW---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0020678",
"lbl": "sensorineural hearing loss disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/sensorineural_hearing_loss"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/9164"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/60700002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0018784"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_10003"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C26739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001176"
}
],
"definition": {
"val": "Hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII).",
"xrefs": [
"Wikipedia:Sensorineural_hearing_loss"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "SNHL",
"xrefs": [
"NCIT:C26739",
"Wikipedia:Sensorineural_hearing_loss"
]
},
{
"pred": "hasExactSynonym",
"val": "sensorineural deafness",
"xrefs": [
"DOID:10003",
"NCIT:C26739"
]
},
{
"pred": "hasExactSynonym",
"val": "sensorineural hearing loss",
"xrefs": [
"DOID:10003",
"NCIT:C26739"
]
},
{
"pred": "hasExactSynonym",
"val": "sensorineural hearing loss disorder"
},
{
"pred": "hasRelatedSynonym",
"val": "neurosensory deafness"
}
],
"xrefs": [
{
"val": "DOID:10003"
},
{
"val": "EFO:1001176"
},
{
"val": "HP:0000407"
},
{
"val": "MEDGEN:9164"
},
{
"val": "NCIT:C26739"
},
{
"val": "SCTID:60700002"
},
{
"val": "UMLS:C0018784"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0020678",
"name": "sensorineural hearing loss disorder",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0020678",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0020678",
"entType": "Disease",
"ldhId": "135642107",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642107",
"modified": "2025-10-07T15:47:06.181Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Y0oy---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/CN043648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#disease_grouping"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
}
],
"xrefs": [
{
"val": "EFO:0009076"
},
{
"val": "DOID:0050563"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:CN043648"
},
{
"val": "GARD:0006410"
},
{
"val": "MESH:C580334"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642097",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642097",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzei--F"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
}
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_disease"
],
"synonyms": [
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush",
"xrefs": [
"Orphanet:886"
]
}
],
"xrefs": [
{
"val": "Orphanet:886"
},
{
"val": "NCIT:C85217"
},
{
"val": "DOID:0050439"
},
{
"val": "OMIMPS:276900"
},
{
"val": "MedDRA:10063396"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MESH:D052245"
},
{
"val": "GARD:0007843"
},
{
"val": "UMLS:C0271097"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642109",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642109",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdm--B"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6750"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1452641873"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/78754"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
}
],
"comments": [
"This term's classification was reviewed in the context of the Strategic Refinement project (2023) and was determined to be excluded from the 'nervous system disorder' (MONDO:0005071) ontology branch (https://orcid.org/0000-0001-9310-0163) and from the 'metabolic disease' (MONDO:0005066) ontology branch (https://orcid.org/0000-0002-1780-5230)"
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush"
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
}
],
"xrefs": [
{
"val": "DOID:0050439"
},
{
"val": "GARD:7843"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:78754"
},
{
"val": "MESH:D052245"
},
{
"val": "MedDRA:10063396"
},
{
"val": "NANDO:1200941"
},
{
"val": "NCIT:C85217"
},
{
"val": "NORD:1816"
},
{
"val": "OMIMPS:276900"
},
{
"val": "Orphanet:886"
},
{
"val": "UMLS:C0271097"
},
{
"val": "icd11.foundation:1452641873"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642100",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642100",
"modified": "2025-10-07T15:46:46.842Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Yhee---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/CN043648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#disease_grouping"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
}
],
"xrefs": [
{
"val": "EFO:0009076"
},
{
"val": "DOID:0050563"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:CN043648"
},
{
"val": "GARD:0006410"
},
{
"val": "MESH:C580334"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss"
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642099",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642099",
"modified": "2023-01-27T21:42:40.716Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHzdi--k"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955117502500,
"agr": "HGNC:7606",
"alias_symbol": [
"NSRD2"
],
"ccds_id": [
"CCDS53684",
"CCDS53683"
],
"date_approved_reserved": "1992-06-08",
"date_modified": "2021-05-26",
"date_name_changed": "2005-09-12",
"ena": [
"U39226"
],
"ensembl_gene_id": "ENSG00000137474",
"entrez_id": "4647",
"gene_group": [
"A-kinase anchoring proteins",
"Myosin heavy chains, class VII",
"FERM domain containing"
],
"gene_group_id": [
396,
1102,
1293
],
"hgnc_id": "HGNC:7606",
"location": "11q13.5",
"location_sortable": "11q13.5",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org/",
"Mutations of the Myosin VIIa Gene|http://www.retina-international.org/files/sci-news/myomut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=MYO7A",
"LRG_1420|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1420.xml"
],
"mane_select": [
"ENST00000409709.9",
"NM_000260.4"
],
"mgd_id": [
"MGI:104510"
],
"name": "myosin VIIA",
"omim_id": [
"276903"
],
"orphanet": 123653,
"prev_name": [
"myosin VIIA (Usher syndrome 1B (autosomal recessive, severe))"
],
"prev_symbol": [
"USH1B",
"DFNB2",
"DFNA11"
],
"pubmed_id": [
8884266
],
"refseq_accession": [
"NM_000260"
],
"rgd_id": [
"RGD:628830"
],
"status": "Approved",
"symbol": "MYO7A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001oyc.3",
"uniprot_ids": [
"Q13402"
],
"uuid": "dba1b3d8-db0d-417e-a168-1285f826aa57",
"vega_id": "OTTHUMG00000152822"
},
"NCBI": {
"id": "4647"
}
},
"entId": "MYO7A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7606",
"entType": "Gene",
"ldhId": "135641853",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641853",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056944316121000,
"agr": "HGNC:13733",
"alias_name": [
"cadherin-related family member 23"
],
"alias_symbol": [
"CDHR23"
],
"ccds_id": [
"CCDS81473",
"CCDS86100",
"CCDS44429",
"CCDS81472",
"CCDS73146",
"CCDS53540"
],
"date_approved_reserved": "2000-10-19",
"date_modified": "2021-05-26",
"date_name_changed": "2016-06-03",
"ena": [
"AY010111"
],
"ensembl_gene_id": "ENSG00000107736",
"entrez_id": "64072",
"gene_group": [
"Cadherin related",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
24,
1691
],
"hgnc_id": "HGNC:13733",
"location": "10q22.1",
"location_sortable": "10q22.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org/",
"Mutations of the Cadherin-related Protein 23 Gene|http://www.retina-international.org/files/sci-news/cdh23mut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=CDH23"
],
"mane_select": [
"ENST00000224721.12",
"NM_022124.6"
],
"mgd_id": [
"MGI:1890219"
],
"name": "cadherin related 23",
"omim_id": [
"605516"
],
"orphanet": 119281,
"prev_name": [
"cadherin-like 23"
],
"prev_symbol": [
"DFNB12",
"USH1D"
],
"pubmed_id": [
11090341
],
"refseq_accession": [
"NM_052836"
],
"rgd_id": [
"RGD:619760"
],
"status": "Approved",
"symbol": "CDH23",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc057twh.2",
"uniprot_ids": [
"Q9H251"
],
"uuid": "dbeb8630-ed09-475e-a5b0-40e2a4a27c29",
"vega_id": "OTTHUMG00000019347"
},
"NCBI": {
"id": "64072"
}
},
"entId": "CDH23",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:13733",
"entType": "Gene",
"ldhId": "135641858",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641858",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyAy--A"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056944971481000,
"agr": "HGNC:2180",
"alias_symbol": [
"COCH-5B2"
],
"ccds_id": [
"CCDS9640",
"CCDS86382"
],
"date_approved_reserved": "1998-10-16",
"date_modified": "2021-05-26",
"date_name_changed": "2013-05-01",
"ensembl_gene_id": "ENSG00000100473",
"entrez_id": "1690",
"hgnc_id": "HGNC:2180",
"location": "14q12",
"location_sortable": "14q12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org"
],
"mane_select": [
"ENST00000396618.9",
"NM_004086.3"
],
"mgd_id": [
"MGI:1278313"
],
"name": "cochlin",
"omim_id": [
"603196"
],
"orphanet": 120681,
"prev_name": [
"coagulation factor C (Limulus polyphemus homolog); cochlin",
"coagulation factor C homolog, cochlin (Limulus polyphemus)"
],
"prev_symbol": [
"DFNA31",
"DFNA9"
],
"pubmed_id": [
9806553
],
"refseq_accession": [
"NM_004086"
],
"rgd_id": [
"RGD:1308536"
],
"status": "Approved",
"symbol": "COCH",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wqr.3",
"uniprot_ids": [
"O43405"
],
"uuid": "a5e29779-7c29-46ca-8ca9-f65eaef96b2b",
"vega_id": "OTTHUMG00000029432"
},
"NCBI": {
"id": "1690"
}
},
"entId": "COCH",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:2180",
"entType": "Gene",
"ldhId": "135641857",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641857",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056964847239200,
"agr": "HGNC:11720",
"ccds_id": [
"CCDS8434"
],
"date_approved_reserved": "1997-08-22",
"date_modified": "2016-10-05",
"ena": [
"AF055136"
],
"ensembl_gene_id": "ENSG00000109927",
"entrez_id": "7007",
"hgnc_id": "HGNC:11720",
"location": "11q23.3",
"location_sortable": "11q23.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org"
],
"mane_select": [
"ENST00000392793.6",
"NM_005422.4"
],
"mgd_id": [
"MGI:109575"
],
"name": "tectorin alpha",
"omim_id": [
"602574"
],
"orphanet": 120015,
"prev_symbol": [
"DFNA12",
"DFNA8",
"DFNB21"
],
"pubmed_id": [
9503015,
9590290
],
"refseq_accession": [
"NM_005422"
],
"rgd_id": [
"RGD:1309824"
],
"status": "Approved",
"symbol": "TECTA",
"ucsc_id": "uc058imn.1",
"uniprot_ids": [
"O75443"
],
"uuid": "04e5bd83-f9dc-46ff-b872-37188a91275d",
"vega_id": "OTTHUMG00000149908"
},
"NCBI": {
"id": "7007"
}
},
"entId": "TECTA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11720",
"entType": "Gene",
"ldhId": "135641850",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641850",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---F"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056955116454000,
"agr": "HGNC:7605",
"alias_symbol": [
"KIAA0389"
],
"ccds_id": [
"CCDS34487",
"CCDS75481"
],
"date_approved_reserved": "1996-04-04",
"date_modified": "2021-05-26",
"date_name_changed": "2004-05-19",
"ena": [
"U90236",
"AB002387"
],
"ensembl_gene_id": "ENSG00000196586",
"entrez_id": "4646",
"gene_group": [
"Myosin heavy chains, class VI"
],
"gene_group_id": [
1101
],
"hgnc_id": "HGNC:7605",
"location": "6q14.1",
"location_sortable": "06q14.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=MYO6",
"LRG_438|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_438.xml"
],
"mane_select": [
"ENST00000369977.8",
"NM_004999.4"
],
"mgd_id": [
"MGI:104785"
],
"name": "myosin VI",
"omim_id": [
"600970"
],
"orphanet": 123648,
"prev_name": [
"deafness, autosomal recessive 37"
],
"prev_symbol": [
"DFNA22",
"DFNB37"
],
"pubmed_id": [
9259267,
11468689
],
"refseq_accession": [
"NM_004999"
],
"rgd_id": [
"RGD:1560646"
],
"status": "Approved",
"symbol": "MYO6",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003pih.2",
"uniprot_ids": [
"Q9UM54"
],
"uuid": "55f734b6-3be2-401d-bfcd-67db81dc9bc7",
"vega_id": "OTTHUMG00000015061"
},
"NCBI": {
"id": "4646"
}
},
"entId": "MYO6",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7605",
"entType": "Gene",
"ldhId": "135641855",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641855",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963218800600,
"agr": "HGNC:8818",
"alias_name": [
"pendrin"
],
"alias_symbol": [
"PDS"
],
"bioparadigms_slc": "SLC26A4",
"ccds_id": [
"CCDS5746"
],
"date_approved_reserved": "1997-10-27",
"date_modified": "2016-10-05",
"date_name_changed": "2016-02-17",
"ena": [
"AF030880"
],
"ensembl_gene_id": "ENSG00000091137",
"entrez_id": "5172",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:8818",
"iuphar": "objectId:1100",
"location": "7q22.3",
"location_sortable": "07q22.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=SLC26A4"
],
"mane_select": [
"ENST00000644269.2",
"NM_000441.2"
],
"mgd_id": [
"MGI:1346029"
],
"name": "solute carrier family 26 member 4",
"omim_id": [
"605646"
],
"orphanet": 118821,
"prev_name": [
"solute carrier family 26, member 4",
"solute carrier family 26 (anion exchanger), member 4"
],
"prev_symbol": [
"DFNB4"
],
"pubmed_id": [
9500541,
11087667
],
"refseq_accession": [
"NM_000441"
],
"rgd_id": [
"RGD:3293"
],
"status": "Approved",
"symbol": "SLC26A4",
"ucsc_id": "uc003vep.4",
"uniprot_ids": [
"O43511"
],
"uuid": "597c9cdf-13fe-4340-9eb0-af0de850ad1c",
"vega_id": "OTTHUMG00000154807"
},
"NCBI": {
"id": "5172"
}
},
"entId": "SLC26A4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8818",
"entType": "Gene",
"ldhId": "135641852",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641852",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056950627500000,
"agr": "HGNC:6298",
"alias_symbol": [
"Kv7.4"
],
"ccds_id": [
"CCDS456"
],
"date_approved_reserved": "1999-02-05",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-04",
"ena": [
"AF105202"
],
"ensembl_gene_id": "ENSG00000117013",
"entrez_id": "9132",
"gene_group": [
"Potassium voltage-gated channels"
],
"gene_group_id": [
274
],
"hgnc_id": "HGNC:6298",
"iuphar": "objectId:563",
"location": "1p34.2",
"location_sortable": "01p34.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1378|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1378.xml"
],
"mane_select": [
"ENST00000347132.10",
"NM_004700.4"
],
"mgd_id": [
"MGI:1926803"
],
"name": "potassium voltage-gated channel subfamily Q member 4",
"omim_id": [
"603537"
],
"orphanet": 122821,
"prev_name": [
"potassium voltage-gated channel, KQT-like subfamily, member 4",
"potassium channel, voltage gated KQT-like subfamily Q, member 4"
],
"prev_symbol": [
"DFNA2"
],
"pubmed_id": [
10025409,
16382104
],
"refseq_accession": [
"NM_004700"
],
"rgd_id": [
"RGD:61799"
],
"status": "Approved",
"symbol": "KCNQ4",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001cgh.2",
"uniprot_ids": [
"P56696"
],
"uuid": "790c26fc-046d-419a-85d7-b1f22f09b567",
"vega_id": "OTTHUMG00000007730"
},
"NCBI": {
"id": "9132"
}
},
"entId": "KCNQ4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6298",
"entType": "Gene",
"ldhId": "135641851",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641851",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056948391936000,
"agr": "HGNC:4284",
"alias_name": [
"connexin 26"
],
"alias_symbol": [
"CX26",
"NSRD1"
],
"ccds_id": [
"CCDS9290"
],
"date_approved_reserved": "1990-02-12",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-09",
"ena": [
"M86849"
],
"ensembl_gene_id": "ENSG00000165474",
"entrez_id": "2706",
"gene_group": [
"Gap junction proteins"
],
"gene_group_id": [
314
],
"hgnc_id": "HGNC:4284",
"iuphar": "objectId:716",
"location": "13q12.11",
"location_sortable": "13q12.11",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"The Connexin-deafness homepage|http://davinci.crg.es/deafness/",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=GJB2",
"LRG_1350|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1350.xml"
],
"mane_select": [
"ENST00000382848.5",
"NM_004004.6"
],
"mgd_id": [
"MGI:95720"
],
"name": "gap junction protein beta 2",
"omim_id": [
"121011"
],
"orphanet": 122129,
"prev_name": [
"gap junction protein, beta 2, 26kD (connexin 26)",
"gap junction protein, beta 2, 26kDa (connexin 26)",
"gap junction protein, beta 2, 26kDa"
],
"prev_symbol": [
"DFNB1",
"DFNA3"
],
"pubmed_id": [
9139825
],
"refseq_accession": [
"NM_004004"
],
"rgd_id": [
"RGD:728891"
],
"status": "Approved",
"symbol": "GJB2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001umy.4",
"uniprot_ids": [
"P29033"
],
"uuid": "91fef4ae-bc30-4ba0-ace1-9a1f58fc5004",
"vega_id": "OTTHUMG00000016513"
},
"NCBI": {
"id": "2706"
}
},
"entId": "GJB2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4284",
"entType": "Gene",
"ldhId": "135641856",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641856",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2---"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056966904545300,
"agr": "HGNC:12601",
"alias_symbol": [
"RP39"
],
"ccds_id": [
"CCDS31025",
"CCDS1516"
],
"date_approved_reserved": "1990-03-06",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-25",
"ena": [
"AF055580"
],
"ensembl_gene_id": "ENSG00000042781",
"entrez_id": "7399",
"gene_group": [
"Fibronectin type III domain containing",
"USH2 complex "
],
"gene_group_id": [
555,
1244
],
"hgnc_id": "HGNC:12601",
"location": "1q41",
"location_sortable": "01q41",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Mutations of the USH2a Gene|http://www.retina-international.org/files/sci-news/ush2amut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=USH2A"
],
"mane_select": [
"ENST00000307340.8",
"NM_206933.4"
],
"mgd_id": [
"MGI:1341292"
],
"name": "usherin",
"omim_id": [
"608400"
],
"orphanet": 120447,
"prev_name": [
"Usher syndrome 2A (autosomal recessive, mild)"
],
"prev_symbol": [
"USH2"
],
"pubmed_id": [
9624053,
10729113
],
"refseq_accession": [
"NM_007123"
],
"rgd_id": [
"RGD:628777"
],
"status": "Approved",
"symbol": "USH2A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001hku.1",
"uniprot_ids": [
"O75445"
],
"uuid": "b1118920-906c-4545-bc00-5b1a4cdb10a4",
"vega_id": "OTTHUMG00000037079"
},
"NCBI": {
"id": "7399"
}
},
"entId": "USH2A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12601",
"entType": "Gene",
"ldhId": "135641854",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641854",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "005_nuclear_CDH23_COCH_GJB2_KCNQ4_MYO6_MYO7A_SLC26A4_TECTA_USH2A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
},
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "CDH23",
"preferredTranscript": "NM_022124.6"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "COCH",
"preferredTranscript": "NM_004086.3"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "GJB2",
"preferredTranscript": "NM_004004.6"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "KCNQ4",
"preferredTranscript": "NM_004700.4"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO6",
"preferredTranscript": "NM_004999.4"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
},
{
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO7A",
"preferredTranscript": "NM_000260.4"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0010134",
"preferredTitle": "Pendred syndrome"
}
],
"gene": "SLC26A4",
"preferredTranscript": "NM_000441.2"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "TECTA",
"preferredTranscript": "NM_005422.4"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
}
],
"gene": "USH2A",
"preferredTranscript": "NM_206933.4"
}
],
"ns": "005",
"references": []
},
"entType": "RuleSet",
"ldhId": "135640633",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640633",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN053",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:40.836Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"053"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN053",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243123",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243123",
"modified": "2022-08-18T19:13:44.249Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN055",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:48.554Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"055"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO7A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN055",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243125",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243125",
"modified": "2022-08-18T19:13:52.009Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--C"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN052",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:36.877Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"052"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GJB2 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN052",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243122",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243122",
"modified": "2022-08-18T19:13:40.396Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN057",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:56.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"057"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TECTA Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN057",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243127",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243127",
"modified": "2022-08-18T19:14:00.553Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN050",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:28.663Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"050"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN050",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243120",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243120",
"modified": "2022-08-18T19:13:32.244Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN058",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:00.973Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"058"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for USH2A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN058",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243128",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243128",
"modified": "2022-08-18T19:14:04.611Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN056",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:52.441Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"056"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC26A4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN056",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243126",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243126",
"modified": "2022-08-18T19:13:56.516Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN054",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:44.669Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"054"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO6 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN054",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243124",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243124",
"modified": "2022-08-18T19:13:48.137Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--B"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN051",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:32.682Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"051"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for COCH Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN051",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243121",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243121",
"modified": "2022-08-18T19:13:36.425Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--_"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "2018-03-02T00:00:00.000Z",
"description": "ACMG variant classification (PAH)",
"namespace": "GN006",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/30311390"
}
],
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "ACMG variant classification (PAH)",
"specificationSource": "https://clinicalgenome.org/docs/clingen-pah-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2018-03-02T00:00:00.000Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-06T18:23:11.454Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-12-05T12:39:42.103Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": true,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-10T17:37:39.725Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"006"
],
"title": "ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0",
"versioned": true
},
"entId": "GN006",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "006_PVS1_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "006",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PVS1 downgraded in strength to Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PVS1 downgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638980",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638980",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--E"
},
{
"entContent": {
"_uniqueProp": "006_PS4_nuclear_PAH",
"additionalComments": "This criterion is not applicable for PAH. For proband counting, use PM3 criterion.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "006",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638979",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638979",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--D"
},
{
"entContent": {
"_uniqueProp": "006_PS3_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "006",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect\n * PAH enzyme activity assay demonstrating enzyme activity <50%\n * RT-PCR evidence of missplicing for non-canonical intronic variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS3 downgraded in strength to Supporting",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638976",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638976",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--D"
},
{
"entContent": {
"_uniqueProp": "006_PS2_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "De novo Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "006",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PS2 downgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638974",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638974",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--F"
},
{
"entContent": {
"_uniqueProp": "006_BP2_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "006",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0084",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638973",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638973",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--L"
},
{
"entContent": {
"_uniqueProp": "006_BP6_nuclear_PAH",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PAH"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "006",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432904",
"modified": "2022-01-19T20:31:30.171Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--J"
},
{
"entContent": {
"_uniqueProp": "006_PM1_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "006",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638987",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638987",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--D"
},
{
"entContent": {
"_uniqueProp": "006_PP3_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "006",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638984",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638984",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--G"
},
{
"entContent": {
"_uniqueProp": "006_BA1_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "006",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.015 (1.5%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638982",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638982",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--G"
},
{
"entContent": {
"_uniqueProp": "006_BP3_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "006",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638975",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638975",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--C"
},
{
"entContent": {
"_uniqueProp": "006_PM4_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "006",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638966",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638966",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--B"
},
{
"entContent": {
"_uniqueProp": "006_PP5_nuclear_PAH",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PAH"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "006",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432905",
"modified": "2022-01-19T20:31:30.171Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--F"
},
{
"entContent": {
"_uniqueProp": "006_PM2_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "006",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n * Threshold: <0.0002 (0.02%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638988",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638988",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--G"
},
{
"entContent": {
"_uniqueProp": "006_PP2_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "006",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638983",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638983",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--E"
},
{
"entContent": {
"_uniqueProp": "006_PP1_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "006",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members:\n * 3 affected segregations + 0 unaffected segregations OR\n * 2 affected segregations + 3 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members\n * 2 affected segregations + 0 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members\n * 1 affected family member + 3 unaffected segregations",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638978",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638978",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--F"
},
{
"entContent": {
"_uniqueProp": "006_BP1_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "006",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638969",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638969",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--C"
},
{
"entContent": {
"_uniqueProp": "006_BS3_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Functional Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "006",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function\n * Enzyme activity >85%",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638967",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638967",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--F"
},
{
"entContent": {
"_uniqueProp": "006_BS1_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "006",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (>0.002, 0.2%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638963",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638963",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--E"
},
{
"entContent": {
"_uniqueProp": "006_PS1_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "006",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638972",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638972",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--E"
},
{
"entContent": {
"_uniqueProp": "006_PM6_nuclear_PAH",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "De novo Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "006",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638971",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638971",
"modified": "2022-01-19T20:33:33.763Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--_"
},
{
"entContent": {
"_uniqueProp": "006_BS4_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "006",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638970",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638970",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--D"
},
{
"entContent": {
"_uniqueProp": "006_PM5_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "006",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638968",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638968",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--C"
},
{
"entContent": {
"_uniqueProp": "006_BS2_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Population Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "006",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638965",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638965",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--E"
},
{
"entContent": {
"_uniqueProp": "006_PP4_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Other Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "006",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Plasma Phe >120 µmol/L and exclusion of a defect of BH4 cofactor metabolism.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638986",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638986",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--H"
},
{
"entContent": {
"_uniqueProp": "006_BP7_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "006",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638985",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638985",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--G"
},
{
"entContent": {
"_uniqueProp": "006_BP5_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Other Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "006",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638981",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638981",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--F"
},
{
"entContent": {
"_uniqueProp": "006_BP4_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "006",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638977",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638977",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq---"
},
{
"entContent": {
"_uniqueProp": "006_PM3_nuclear_PAH",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009861"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PAH"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "006",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "For recessive disorders, detected in trans with a pathogenic variant.\n * 4 compound heterozygotes with 3 P/LP variants OR\n * 2 compound heterozygotes with 2 P/LP variants AND 4 homozygotes OR\n * 3 compound heterozygotes with 2 P/LP variants AND 2 homozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "For recessive disorders, detected in trans with a pathogenic variant.\n * Compound heterozygous with 2 P/LP variants OR\n * Compound heterozygous with 1 P/LP variant AND 2 homozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For recessive disorders, detected in trans with a pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Detected in trans with another variant:\n * 2 compound heterozygotes (with VUS in trans)\n * 2 homozygotes (allele drop out excluded)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638964",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638964",
"modified": "2021-11-05T21:07:12.308Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--D"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009861",
"lbl": "phenylketonuria",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4985"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009861"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/phenylketonuria"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10034872"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/444122923"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/19244"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D010661"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/7573000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0031485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_9281"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C81315"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_716"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/261600"
}
],
"definition": {
"val": "Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and is characterized by mild to severe mental disability in untreated patients.",
"xrefs": [
"Orphanet:716"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "PAH deficiency",
"xrefs": [
"OMIM:261600",
"Orphanet:716"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PKU",
"xrefs": [
"DOID:9281",
"MONDO:Lexical",
"NCIT:C81315",
"OMIM:261600",
"Orphanet:716"
]
},
{
"pred": "hasExactSynonym",
"val": "hyperphenylalaninemia, non-PKU mild"
},
{
"pred": "hasExactSynonym",
"val": "phenylalanine hydroxylase deficiency",
"xrefs": [
"OMIM:261600",
"Orphanet:716",
"icd11.foundation:444122923"
]
},
{
"pred": "hasExactSynonym",
"val": "phenylalaninemia",
"xrefs": [
"DOID:9281"
]
},
{
"pred": "hasExactSynonym",
"val": "phenylketonuria",
"xrefs": [
"DOID:9281",
"MONDO:Lexical",
"NCIT:C81315",
"OMIM:261600",
"Orphanet:716",
"icd11.foundation:444122923"
]
},
{
"pred": "hasRelatedSynonym",
"val": "HPA, non-PKU mild"
},
{
"pred": "hasRelatedSynonym",
"val": "imbecilitus phenylpyruvica"
},
{
"pred": "hasRelatedSynonym",
"val": "oligophrenia Phenylpyruvica"
},
{
"pred": "hasRelatedSynonym",
"val": "oligophrenia phenylpyruvica"
},
{
"pred": "hasRelatedSynonym",
"val": "phenylketonuria, maternal"
},
{
"pred": "hasRelatedSynonym",
"val": "phenylpyruvic oligophrenia"
}
],
"xrefs": [
{
"val": "DOID:9281"
},
{
"val": "GARD:7383"
},
{
"val": "ICD9:270.1"
},
{
"val": "MEDGEN:19244"
},
{
"val": "MESH:D010661"
},
{
"val": "MedDRA:10034872"
},
{
"val": "NANDO:1200784"
},
{
"val": "NANDO:1200785"
},
{
"val": "NANDO:2200467"
},
{
"val": "NANDO:2201075"
},
{
"val": "NCIT:C81315"
},
{
"val": "NORD:1574"
},
{
"val": "OMIM:261600"
},
{
"val": "Orphanet:716"
},
{
"val": "SCTID:7573000"
},
{
"val": "UMLS:C0031485"
},
{
"val": "icd11.foundation:444122923"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009861",
"name": "phenylketonuria",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0009861",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009861",
"entType": "Disease",
"ldhId": "135642146",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642146",
"modified": "2025-10-07T15:44:02.594Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WBPi---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056956991307800,
"agr": "HGNC:8582",
"alias_name": [
"phenylalanine 4-monooxygenase"
],
"alias_symbol": [
"PH"
],
"ccds_id": [
"CCDS9092"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2016-01-15",
"ena": [
"U49897"
],
"ensembl_gene_id": "ENSG00000171759",
"entrez_id": "5053",
"enzyme_id": [
"1.14.16.1"
],
"hgnc_id": "HGNC:8582",
"iuphar": "objectId:1240",
"location": "12q23.2",
"location_sortable": "12q23.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Phenylalanine Hydroxylase Locus Knowledgebase|http://www.pahdb.mcgill.ca"
],
"mane_select": [
"ENST00000553106.6",
"NM_000277.3"
],
"mgd_id": [
"MGI:97473"
],
"name": "phenylalanine hydroxylase",
"omim_id": [
"612349"
],
"orphanet": 124068,
"pubmed_id": [
2063869
],
"refseq_accession": [
"NM_000277"
],
"rgd_id": [
"RGD:3248"
],
"status": "Approved",
"symbol": "PAH",
"ucsc_id": "uc001tjq.2",
"uniprot_ids": [
"P00439"
],
"uuid": "cc17518f-1d35-4953-ab6e-ff91c46ae4c5",
"vega_id": "OTTHUMG00000169966"
},
"NCBI": {
"id": "5053"
}
},
"entId": "PAH",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8582",
"entType": "Gene",
"ldhId": "135641880",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641880",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "006_nuclear_PAH",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0009861",
"preferredTitle": "phenylketonuria"
}
],
"gene": "PAH"
}
],
"ns": "006"
},
"entType": "RuleSet",
"ldhId": "135640693",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640693",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--D"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2018-04-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-04-27T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Phenylketonuria",
"shortBaseName": "PAH",
"shortTitle": "Phenylketonuria VCEP",
"title": "Phenylketonuria Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50015",
"entIri": "http://clinicalgenome.org/affiliation/50015",
"entType": "Organization",
"ldhId": "135637639",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637639",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--F"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637578",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637578",
"modified": "2024-03-10T17:37:40.064Z",
"modifier": "sharriso",
"rev": "_h6SHyk---O"
},
{
"entContent": {
"approvedOn": "2024-10-30T12:32:26.289Z",
"description": "This version specified for the following genes: CDH1",
"namespace": "GN007",
"releaseNotes": "(1) Specification of PM5\\_Supporting to nonsense and frameshift variants that are predicted/proved to undergo nonsense-mediated decay (NMD) or located upstream of the last known pathogenic truncating variant \\[c.2506G>T (p.Glu836Ter)\\]. \n(2) Column correction for PM2\\_Supporting from Moderate column to Supporting column.",
"releasedUnderRevision": true,
"shortTitle": "CDH1 Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-10-30T12:32:26.289Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-04-03T19:03:16.703Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecVcepCoordinatorTest",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-10-30T12:31:13.028Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "cspecSviApproverTest",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-10-30T12:32:14.199Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"007"
],
"title": "ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH1 Version 3.2.0",
"version": "3.2.0",
"versioned": true
},
"entId": "GN007",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "007_PP5_nuclear_CDH1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "007",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432935",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432935",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntdG---"
},
{
"entContent": {
"_uniqueProp": "007_PM2_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use gnomAD to determine allele frequency. The mean coverage of CDH1 in the population database used should be at least 30x.",
"label": "PM2",
"ns": "007",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639069",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639069",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntWS--B"
},
{
"entContent": {
"_uniqueProp": "007_PP2_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "007",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639064",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639064",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntXK---"
},
{
"entContent": {
"_uniqueProp": "007_BP5_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "007",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Per original ACMG/AMP guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639062",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639062",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntY6---"
},
{
"entContent": {
"_uniqueProp": "007_PS1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "007",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639053",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639053",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntVC---"
},
{
"entContent": {
"_uniqueProp": "007_BS4_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Beware of the presence of phenocopies (e.g., breast cancer) that can mimic lack of segregation. Also, families may have more than one pathogenic variant contributing to another AD disorder.",
"label": "BS4",
"ns": "007",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Per original ACMG/AMP guidelines.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639051",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639051",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irznteW---"
},
{
"entContent": {
"_uniqueProp": "007_BS3_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule can only be used to demonstrate lack of splicing and can only be applied to Synonymous, Intronic or Non-coding variants. BS3 may be downgraded based on quality of data.",
"label": "BS3",
"ns": "007",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Functional RNA studies demonstrating no impact on transcript composition.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639048",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639048",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntZq---"
},
{
"entContent": {
"_uniqueProp": "007_BP6_nuclear_CDH1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "007",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432934",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432934",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntfe---"
},
{
"entContent": {
"_uniqueProp": "007_PP4_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "007",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639067",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639067",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntZ6---"
},
{
"entContent": {
"_uniqueProp": "007_BA1_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must ≥ 2,000 alleles and have a minimum of five variant alleles present.",
"label": "BA1",
"ns": "007",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of 0.2%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639063",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639063",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntQO---"
},
{
"entContent": {
"_uniqueProp": "007_PS4_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use the 2020 updated clinical practice guidelines (PMID: 32758476) as the HDGC phenotype criteria.\nPS4 cannot be applied to variants that meet BS1 or BA1, or to variants in which less than 30% of reported individuals meet HDGC criteria.",
"label": "PS4",
"ns": "007",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥Sixteen families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Four - Fifteen families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Two or three families meet HDGC criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One family meets HDGC criteria.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639060",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639060",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntQ2---"
},
{
"entContent": {
"_uniqueProp": "007_BP7_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Note the CDH1 rule specification does not require a conservation prediction. We allow use of BP7 with BP4, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "007",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Synonymous and intronic variants at or beyond +7 to -21 locations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639066",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639066",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntXa---"
},
{
"entContent": {
"_uniqueProp": "007_PP3_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "PP3 cannot be applied for canonical splice sites. PP3 code also does not apply to the last nucleotide of exon 3 (c.387G). Do not use protein-based computational prediction models for missense variants.",
"label": "PP3",
"ns": "007",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639065",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639065",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntbO---"
},
{
"entContent": {
"_uniqueProp": "007_PVS1_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "RNA analysis is recommended for splicing alterations, and if the RNA evidence does not support the prediction, the strength should be updated.",
"label": "PVS1",
"ns": "007",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per modified CDH1 PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. \n * CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per modified CDH1 PVS1 decision tree.\nOther CDH1 caveats:\n * G to non-G variants disrupting the last nucleotide of an exon.\n * Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639061",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639061",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irznteG---"
},
{
"entContent": {
"_uniqueProp": "007_PP1_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Based strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "007",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥Seven informative meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Five-six informative meioses across ≥1 family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Three-four informative meioses across ≥1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639059",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639059",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntSy---"
},
{
"entContent": {
"_uniqueProp": "007_BP3_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "007",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639056",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639056",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntc----"
},
{
"entContent": {
"_uniqueProp": "007_PS2_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype (see Table S2).",
"label": "PS2",
"ns": "007",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "One patient meets the HDGC individual phenotype criteria w/ parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639055",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639055",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irznte6---"
},
{
"entContent": {
"_uniqueProp": "007_PM5_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "The nonsense or frameshift variant must not impact splicing based on RNA assay or splicing predictions.",
"label": "PM5",
"ns": "007",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639049",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639049",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntaq---"
},
{
"entContent": {
"_uniqueProp": "007_PM4_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "PM4 is not applied to small in-frame indels because the impact of amino acid level changes of CDH1 variants is inconclusive.",
"label": "PM4",
"ns": "007",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Only apply to stop-loss variants\nVariant example: CDH1 c.2647T>C (p.Ter883Glnext*29).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639047",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639047",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntYG--F"
},
{
"entContent": {
"_uniqueProp": "007_BS2_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "We allow a variant to reach a likely benign classification based on BS2 alone.\nBS2 cannot be applied to variants in which more than 30% of reported individuals meet HDGC criteria.",
"label": "BS2",
"ns": "007",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639046",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639046",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntPe---"
},
{
"entContent": {
"_uniqueProp": "007_PM3_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "007",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639045",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639045",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntRu---"
},
{
"entContent": {
"_uniqueProp": "007_BS1_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must ≥ 2,000 alleles and have a minimum of five variant alleles present. We allow a variant to reach a likely benign classification based on BS1 alone.",
"label": "BS1",
"ns": "007",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF cutoff of 0.1%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639044",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639044",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntVi---"
},
{
"entContent": {
"_uniqueProp": "007_BP4_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use protein based computational prediction models and BP4 is not applicable for missense variants.",
"label": "BP4",
"ns": "007",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639058",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639058",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntRG---"
},
{
"entContent": {
"_uniqueProp": "007_PM6_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "007",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": ">Four patients meet the HDGC individual phenotype criteria w/o parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "One patient meets the HDGC individual phenotype criteria w/o parental confirmation",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639052",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639052",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntgC---"
},
{
"entContent": {
"_uniqueProp": "007_PM1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "007",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639068",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639068",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntUS---"
},
{
"entContent": {
"_uniqueProp": "007_PS3_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule can only be applied to demonstrate splicing defects.",
"label": "PS3",
"ns": "007",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "RNA assay demonstrating abnormal out-of-frame transcripts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "RNA assay demonstrating abnormal in-frame transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639057",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639057",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntcm---"
},
{
"entContent": {
"_uniqueProp": "007_BP2_nuclear_CDH1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "007",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant is observed in cis (or phase is unknown) w/ a pathogenic variant\nOR observed in the homozygous state in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639054",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639054",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntTW---"
},
{
"entContent": {
"_uniqueProp": "007_BP1_nuclear_CDH1",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDH1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "007",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639050",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639050",
"modified": "2024-10-30T12:32:27.335Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntTy---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007648",
"lbl": "hereditary diffuse gastric adenocarcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5720"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007648"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/diffuse_gastric_and_lobular_breast_cancer_syndrome"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10334/diffuse-gastric-cancer"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10900/hereditary-diffuse-gastric-cancer"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/310839"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/716859000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1708349"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080764"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C43295"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_26106"
}
],
"definition": {
"val": "An autosomal dominant inherited adenocarcinoma that arises from the gastric mucosa and is characterized by the presence of poorly cohesive malignant cells and absence of glandular formations.",
"xrefs": [
"NCIT:C43295"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "FDGC",
"xrefs": [
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "HDGC",
"xrefs": [
"MONDO:Lexical",
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"val": "familial diffuse cancer of stomach",
"xrefs": [
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"val": "familial diffuse gastric cancer",
"xrefs": [
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary diffuse cancer of stomach",
"xrefs": [
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary diffuse gastric adenocarcinoma",
"xrefs": [
"MONDO:patterns/hereditary",
"NCIT:C43295",
"Orphanet:26106"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary diffuse gastric cancer",
"xrefs": [
"DOID:0080764",
"NCIT:C43295",
"Orphanet:26106"
]
},
{
"pred": "hasRelatedSynonym",
"val": "diffuse gastric cancer",
"xrefs": [
"GARD:0010334"
]
},
{
"pred": "hasRelatedSynonym",
"val": "signet cell adenocarcinoma",
"xrefs": [
"GARD:0010334"
]
},
{
"pred": "hasRelatedSynonym",
"val": "signet ring cell gastric carcinoma",
"xrefs": [
"GARD:0010334"
]
},
{
"pred": "hasRelatedSynonym",
"val": "signet ring gastric carcinoma",
"xrefs": [
"GARD:0010334"
]
}
],
"xrefs": [
{
"val": "DOID:0080764"
},
{
"val": "GARD:10900"
},
{
"val": "MEDGEN:310839"
},
{
"val": "NCIT:C43295"
},
{
"val": "Orphanet:26106"
},
{
"val": "SCTID:716859000"
},
{
"val": "UMLS:C1708349"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007648",
"name": "hereditary diffuse gastric adenocarcinoma",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0007648",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007648",
"entType": "Disease",
"ldhId": "135642152",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642152",
"modified": "2025-10-07T15:43:30.403Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vhwe---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056944300392400,
"agr": "HGNC:1748",
"alias_name": [
"E-Cadherin"
],
"alias_symbol": [
"uvomorulin",
"CD324"
],
"ccds_id": [
"CCDS82005",
"CCDS10869"
],
"cd": "CD324",
"cosmic": "CDH1",
"curator_notes": [
"This entry has the approved symbol CDH1 which is also an alias symbol for the unrelated gene [FZR1](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:24824)."
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-15",
"ena": [
"L08599"
],
"ensembl_gene_id": "ENSG00000039068",
"entrez_id": "999",
"gene_group": [
"CD molecules",
"Type I classical cadherins"
],
"gene_group_id": [
471,
1185
],
"hgnc_id": "HGNC:1748",
"location": "16q22.1",
"location_sortable": "16q22.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_301|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_301.xml"
],
"mane_select": [
"ENST00000261769.10",
"NM_004360.5"
],
"mgd_id": [
"MGI:88354"
],
"name": "cadherin 1",
"omim_id": [
"192090"
],
"orphanet": 119276,
"prev_name": [
"cadherin 1, type 1, E-cadherin (epithelial)"
],
"prev_symbol": [
"UVO"
],
"pubmed_id": [
9925936
],
"refseq_accession": [
"NM_004360"
],
"rgd_id": [
"RGD:69279"
],
"status": "Approved",
"symbol": "CDH1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002ewg.2",
"uniprot_ids": [
"P12830"
],
"uuid": "8c24df1c-92f1-4bf0-9dbc-6bb750d4f288",
"vega_id": "OTTHUMG00000137561"
},
"NCBI": {
"id": "999"
}
},
"entId": "CDH1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1748",
"entType": "Gene",
"ldhId": "135641886",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641886",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "007_nuclear_CDH1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"modesOfInheritance": [
{
"modeOfInheritance": "Autosomal dominant inheritance"
}
],
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0007648",
"preferredTitle": "hereditary diffuse gastric cancer"
}
],
"gene": "CDH1",
"preferredTranscript": "NM_004360.5",
"transcripts": [
"NM_004360.5"
]
}
],
"ns": "007",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM4",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP2_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP2_Strong"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "135640753",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640753",
"modified": "2024-10-30T12:32:27.158Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzntBq---"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approvalDate": "2018-09-04T00:00:00.000Z",
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Gastric Cancer",
"shortBaseName": "Gastric Cancer",
"shortTitle": "Gastric Cancer VCEP",
"title": "Gastric Cancer Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel",
"vcepNameTrail": [
{
"deprecated": "2025-02-19T00:00:00.000Z",
"shortTitle": "CDH1 VCEP",
"title": "CDH1 Variant Curation Expert Panel"
}
]
},
"entId": "50014",
"entIri": "http://clinicalgenome.org/affiliation/50014",
"entType": "Organization",
"ldhId": "135637638",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637638",
"modified": "2025-05-13T13:00:29.886Z",
"modifier": "cspecAdministrator",
"rev": "_jqk5dSm---"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637579",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637579",
"modified": "2024-10-30T12:32:26.996Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_irzns3e---"
},
{
"entContent": {
"approvedOn": "2021-09-15T00:00:00.000Z",
"description": "MM-VCEP ACMG/AMP specifications for RUNX1",
"namespace": "GN008",
"releaseNotes": "\n(1) New REVEL thresholds for PP3 ≥ 0.88 and for BP4 ≤ 0.50 (originally PP3 ≥ 0.75 and BP4 ≤ 0.15).\n(2) Use SpliceAI as the primary in-silico splicing predictor replacing MES and SSF. The thresholds for SpliceAI ≥ 0.38 for PP3 and ≤ 0.20 for BP4. \n(3) PP3 can be applied for missense, synonymous, intronic and non-coding variants if the variant impacts splicing, including the creation of cryptic novel splice sites.\n(4) New conservation threshold for phyloP100 way (GRCh38/hg38) ≤2.0 for BP7 (originally PhyloP score < 0.1).\n(5) New amino acid range for PM1_supporting and PM4_supporting to AA 89-204 (originally AA105-204).\n(6) Apply PM5_supporting to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).\n(7) PM2 is downgraded to PM2_supporting.\n(8) Use of the Bayesian point system in curations with conflicting evidence.\n(9) Remove the previous location requirements (+7/-21 in BP7 and ±3/±5 in PP3) for intronic variants in BP7 and PP3. And remove the usage for UTR variants in PP3/BP4/BP7.\n",
"shortTitle": "Myeloid Malignancy Specification",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50034/docs/assertion-criteria ",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-09-15T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"008"
],
"title": "ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0"
},
"entId": "GN008",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "008_PP5_nuclear_RUNX1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RUNX1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "008",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432965",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432965",
"modified": "2022-01-19T20:31:30.801Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--G"
},
{
"entContent": {
"_uniqueProp": "008_PM2_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "008",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant must be completely absent from all population databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639150",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639150",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--G"
},
{
"entContent": {
"_uniqueProp": "008_BS3_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "008",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Transactivation assays demonstrating normal transactivation (80- 115% of wt) AND data from a secondary assay demonstrating normal function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Transactivation assays demonstrating normal transactivation (80- 115% of wt).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639129",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639129",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--M"
},
{
"entContent": {
"_uniqueProp": "008_PM4_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "008",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0059",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In-frame deletion/insertion impacting at least one of the other amino acid residues 89-204 within the RHD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639128",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639128",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--K"
},
{
"entContent": {
"_uniqueProp": "008_BP4_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "008",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants: REVEL score <0.50 AND SpliceAI ≤ 0.20.\nFor synonymous and Intronic variants: SpliceAI ≤ 0.20.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639139",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639139",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi---"
},
{
"entContent": {
"_uniqueProp": "008_BP3_nuclear_RUNX1",
"additionalComments": "RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "008",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639137",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639137",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--F"
},
{
"entContent": {
"_uniqueProp": "008_PS1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "008",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0046",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639134",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639134",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--D"
},
{
"entContent": {
"_uniqueProp": "008_PM6_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "008",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nModerate = 1.0 points total.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639133",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639133",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--J"
},
{
"entContent": {
"_uniqueProp": "008_PM5_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "008",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0056",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before. Not applicable in combination with PM1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change which has been determined to be pathogenic before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0048",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change which has been determined to be likely pathogenic before. PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639130",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639130",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--L"
},
{
"entContent": {
"_uniqueProp": "008_PP4_nuclear_RUNX1",
"additionalComments": "The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "008",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639148",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639148",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--a"
},
{
"entContent": {
"_uniqueProp": "008_PVS1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "008",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639142",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639142",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--C"
},
{
"entContent": {
"_uniqueProp": "008_PP1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "008",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 7 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3 or 4 meioses observed within one or across multiple families.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639140",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639140",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--K"
},
{
"entContent": {
"_uniqueProp": "008_PS2_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "008",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nModerate = 1.0 points total.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.\nSupporting = 0.5 points total.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639136",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639136",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--I"
},
{
"entContent": {
"_uniqueProp": "008_BP2_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "008",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639135",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639135",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--H"
},
{
"entContent": {
"_uniqueProp": "008_BP6_nuclear_RUNX1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RUNX1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "008",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432964",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432964",
"modified": "2022-01-19T20:31:30.801Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--K"
},
{
"entContent": {
"_uniqueProp": "008_BP7_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "008",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved phyloP100 way (GRCh38/hg38) ≤2.0).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639147",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639147",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--_"
},
{
"entContent": {
"_uniqueProp": "008_BP5_nuclear_RUNX1",
"additionalComments": "BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "008",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639143",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639143",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--X"
},
{
"entContent": {
"_uniqueProp": "008_PS4_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "008",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 probands meeting at least one of the RUNX1-phenotypic criteria.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 proband meeting at least one of the RUNX1-phenotypic criteria.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639141",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639141",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--E"
},
{
"entContent": {
"_uniqueProp": "008_BS4_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "008",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "General recommendation",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applied when seen in ≥ 2 informative meioses.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639132",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639132",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq---"
},
{
"entContent": {
"_uniqueProp": "008_BS2_nuclear_RUNX1",
"additionalComments": "BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "008",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639127",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639127",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--N"
},
{
"entContent": {
"_uniqueProp": "008_PM1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "008",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Gene-Specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": " Variant affecting one of the following amino acid residues within he RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0054",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant affecting one of the other amino acid residues 89-204 within the RHD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639149",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639149",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--F"
},
{
"entContent": {
"_uniqueProp": "008_PP3_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "008",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants: REVEL score ≥ 0.88.\nFor missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639146",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639146",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--M"
},
{
"entContent": {
"_uniqueProp": "008_PP2_nuclear_RUNX1",
"additionalComments": "The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "008",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639145",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639145",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--Y"
},
{
"entContent": {
"_uniqueProp": "008_BA1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "008",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639144",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639144",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--B"
},
{
"entContent": {
"_uniqueProp": "008_PS3_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "008",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Transactivation assays demonstrating altered transactivation (<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Transactivation assays demonstrating enhanced transactivation (>115% of wt).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639138",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639138",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--A"
},
{
"entContent": {
"_uniqueProp": "008_BP1_nuclear_RUNX1",
"additionalComments": "BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "008",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639131",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639131",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq---"
},
{
"entContent": {
"_uniqueProp": "008_PM3_nuclear_RUNX1",
"additionalComments": "FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "008",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639126",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639126",
"modified": "2022-01-19T20:33:34.026Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--B"
},
{
"entContent": {
"_uniqueProp": "008_BS1_nuclear_RUNX1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"RUNX1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "008",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639125",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639125",
"modified": "2021-11-05T21:10:25.567Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--L"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011071",
"lbl": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8567"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0011071"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/platelet_disorder_familial_with_associated_myeloid_malignancy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C563324"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/725034002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C162696"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_71290"
}
],
"definition": {
"val": "The disorder is characterized by thrombocytopenia of varying severity and a predisposition to hematologic malignancies. It may be caused due to germ line variations in the RUNX1, ETV6 or ANKRD26 genes.",
"xrefs": [
"PMID:28600339",
"https://clinicalgenome.org/affiliation/50034/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "familial platelet syndrome with predisposition to acute myelogenous leukaemia"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "familial thrombocytopenia with propensity to acute myelogenous leukaemia"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "thrombocytopenia, familial, with propensity to acute myelogenous leukaemia"
}
],
"xrefs": [
{
"val": "GARD:10352"
},
{
"val": "MESH:C563324"
},
{
"val": "NCIT:C162696"
},
{
"val": "Orphanet:71290"
},
{
"val": "SCTID:725034002"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011071",
"name": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0011071",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011071",
"entType": "Disease",
"ldhId": "135642158",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642158",
"modified": "2025-10-07T15:44:21.975Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WUNe---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962288713700,
"agr": "HGNC:10471",
"alias_name": [
"aml1 oncogene"
],
"alias_symbol": [
"PEBP2A2",
"AMLCR1"
],
"ccds_id": [
"CCDS42922",
"CCDS46646",
"CCDS13639"
],
"cosmic": "RUNX1",
"date_approved_reserved": "1991-08-20",
"date_modified": "2021-05-26",
"date_name_changed": "2019-04-04",
"ena": [
"X79549"
],
"ensembl_gene_id": "ENSG00000159216",
"entrez_id": "861",
"gene_group": [
"Runt-related transcription factors"
],
"gene_group_id": [
1880
],
"hgnc_id": "HGNC:10471",
"location": "21q22.12",
"location_sortable": "21q22.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_482|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_482.xml"
],
"mane_select": [
"ENST00000675419.1",
"NM_001754.5"
],
"mgd_id": [
"MGI:99852"
],
"name": "RUNX family transcription factor 1",
"omim_id": [
"151385"
],
"orphanet": 118423,
"prev_name": [
"acute myeloid leukemia 1",
"runt-related transcription factor 1",
"runt related transcription factor 1"
],
"prev_symbol": [
"AML1",
"CBFA2"
],
"pubmed_id": [
1427868,
7835892
],
"refseq_accession": [
"NM_001001890"
],
"rgd_id": [
"RGD:2283"
],
"status": "Approved",
"symbol": "RUNX1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002yuk.6",
"uniprot_ids": [
"Q01196"
],
"uuid": "c47a38f6-4c38-4523-bf1c-1567b75f391d",
"vega_id": "OTTHUMG00000086299"
},
"NCBI": {
"id": "861"
}
},
"entId": "RUNX1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10471",
"entType": "Gene",
"ldhId": "135641893",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641893",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "008_nuclear_RUNX1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0011071",
"preferredTitle": "hereditary thrombocytopenia and hematologic cancer predisposition syndrome"
}
],
"gene": "RUNX1",
"preferredTranscript": "NM_001754.4 (RUNX1c)"
}
],
"ns": "008",
"references": []
},
"entType": "RuleSet",
"ldhId": "135640813",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640813",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--_"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-06-13T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-01-25T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2019-07-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2019-07-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Myeloid Malignancy",
"shortBaseName": "MyeloMalig",
"shortTitle": "Myeloid Malignancy VCEP",
"title": "Myeloid Malignancy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50034",
"entIri": "http://clinicalgenome.org/affiliation/50034",
"entType": "Organization",
"ldhId": "135637650",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637650",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--X"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637580",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637580",
"modified": "2023-09-29T15:16:45.795Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--H"
},
{
"entContent": {
"approvedOn": "2024-03-28T18:26:03.720Z",
"description": "TP53 Rule Specifications for the ACMG/AMP Variant Curation Guidelines",
"namespace": "GN009",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/33300245/"
}
],
"releaseNotes": "1. Major version 2 VCEP updates with SVI feedback from first submission incorporated\n2. Points based evidence combining criteria based on modified Bayesian points system\n3. V2 Pilot added for SVI review",
"releasedUnderRevision": true,
"shortTitle": "TP53 VCEP ACMG/AMP Specifications",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-28T18:26:03.720Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-08-08T17:58:02.852Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-18T14:13:49.380Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-28T18:25:50.965Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-07T19:00:30.101Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-16T19:42:02.220Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"009"
],
"title": "ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0",
"version": "2.0.0",
"versioned": true
},
"entId": "GN009",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "009_PM1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "There are several known major hotspots for the _TP53_ gene. This code can be used for variants within the following codons using canonical transcript NM\\_000546.4: 175, 245, 248, 249, 273, 282\n\nThis code can also be used for germline missense variants seen in cancerhotspots.org (v2) with ≥ 10 somatic occurrences for the same amino acid change. This follows the recommendation from the ClinGen Germline/Somatic Variant Curation Subcommittee (PMID: 30311369).",
"label": "PM1",
"ns": "009",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variants within the following codons using transcript NM\\_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639230",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639230",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuG--F"
},
{
"entContent": {
"_uniqueProp": "009_PVS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "009",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID: 30192042) the following will apply:\n\n* Initiation codon:\n * PVS1 may be applied to initiation codon variants\n* Nonsense or frameshift variants:\n * PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351\n * PVS1\\_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range\n * PVS1\\_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range\n * PVS1\\_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon\n* Canonical splice variants (+/- 1,2 intronic positions): \n * PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)\n * PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)\n * PVS1\\_Moderate applied to splicing alterations that are predicted to shorten (\\<10% of the protein removed) or expand a _TP53_ C-terminal end of unknown function (E10 donor or E11 acceptor)\n* Deletions\n * Full gene deletions: PVS1\n * Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1\n * Single- to multi-exon deletion that disrupts the reading frame and is **NOT** predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1\n * Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1\n * If the role of the region in protein function is unknown, if the variant removed \\< 10% of the protein (deletion of exon 11): PVS1\\_Moderate\n * Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1\n* Duplications (≥1 exon in size and must be completely contained within the _TP53_ gene)\n * Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\n * Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1\\_Strong\n\nFor variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1\\_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.\n\n_Caveats_: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.\n\nFor the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:\n\n**TAD1**: aa 17-25\n\n**TAD2**: aa 48-56\n\n**Proline residues**: aa 64-92\n\n**DNA binding domain**: aa 100-292\n\n**Hinge domain**: aa 293-324\n\n**Oligomerization domain**: aa 325-356\n\n**C-terminal domain (Basic domain)**: aa 368-387\n\nA disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for _TP53_ PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639223",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639223",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxue--_"
},
{
"entContent": {
"_uniqueProp": "009_PS2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "_De novo_ points should be tallied using the table for tallying proband points based on whether maternity and paternity have been confirmed and the type of cancer(s) seen in the proband. This includes probands that are confirmed constitutional mosaics (low _TP53_ VAF on blood or buccal testing with the mutation detected in non-lymphocyte tissue and/or segregating in other family members). For probands with multiple cancers, use the most specific/highest weight cancer to determine point application for that proband. Points for all probands should be tallied to determine the strength of PS2 code application, consistent with SVI guidance. To avoid redundancy and increase consistency, the _TP53_ VCEP has opted to drop PM6 and use PS2 exclusively for _de novo_ evidence.\n\nA Table for LFS Cancers for PS2 (and PP1) code application is included below",
"label": "PS2",
"ns": "009",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639217",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639217",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--J"
},
{
"entContent": {
"_uniqueProp": "009_BP7_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP7",
"ns": "009",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639228",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639228",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqe--B"
},
{
"entContent": {
"_uniqueProp": "009_BP6_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432994",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432994",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxp2--C"
},
{
"entContent": {
"_uniqueProp": "009_PP2_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "009",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639226",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639226",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuW--_"
},
{
"entContent": {
"_uniqueProp": "009_PM3_nuclear_TP53",
"additionalComments": "This rule does not apply to TP53/Li-Fraumeni syndrome.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "009",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639207",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639207",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpW---"
},
{
"entContent": {
"_uniqueProp": "009_PS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This rule code can only be used to compare variants asserted as pathogenic or likely pathogenic following the ClinGen _TP53_ VCEP’s specifications. Must confirm there is no difference using RNA data or SpliceAI (SpliceAI \\< 0.2). Caveat: If both PS1 and PM5 are met, apply the strongest weight possible for each rule code not to exceed a combined strength of strong (4 points in total).",
"label": "PS1",
"ns": "009",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Can be applied to variants asserted as Pathogenic following the _TP53_ VCEP’s specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Can be applied to variants asserted as Likely Pathogenic following the _TP53_ VCEP’s specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639215",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639215",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--H"
},
{
"entContent": {
"_uniqueProp": "009_BP2_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": [
"Evidence code can be applied in either scenario: Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR when there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two differemt pathogenic or likely pathogenic TP53 variants."
],
"label": "BP2",
"ns": "009",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639216",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639216",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqW---"
},
{
"entContent": {
"_uniqueProp": "009_PP5_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432995",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432995",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuK--_"
},
{
"entContent": {
"_uniqueProp": "009_PS4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "There are two widely used clinical criteria for assessing the likelihood of Li Fraumeni syndrome - Classical and Chompret criteria - with the Chompret criteria being less restrictive. Individuals who meet the Revised Chompret criteria have an estimated ~30% risk of harboring a pathogenic _TP53_ variant (Bougeard et al., 2015; PMID: 26014290). Members of the _TP53_ VCEP calculated likelihood ratios (LRs) for patients meeting Classic LFS or Revised Chompret criteria (excluding confirmed constitutional mosaics) using multigene panel testing from Ambry Genetics laboratory. Our data demonstrated that individuals meeting Revised Chompret criteria had a LR of > 2.08 to ≤ 4.3 and individuals meeting Classic LFS criteria had a LR of > 4.3 to ≤ 18.7. Therefore, **we recommend that probands with** _**TP53**_ **germline variants meeting Revised Chompret should be given 0.5 point and probands meeting Classic LFS criteria should be given 1 point.** Do not apply this code for probands with _de novo_ TP53 variants, in which case PS2\\_Variable Weight should be applied instead.\n\nEarly-onset breast cancer is the most common malignancy in women with LFS. Breast tumors from _TP53_ carriers are more likely to be HER2+ than those of non-carriers. Fortuno et al., 2020 (PMID: 32485079) investigated if breast tumor HER2 status has utility as a predictor of _TP53_ germline variant pathogenicity considering age at diagnosis. Their results showed that the identification of HER2+ breast tumors diagnosed before age 40 equated to Supporting level towards pathogenicity and therefore can be incorporated into _TP53_ criteria. **Unrelated probands who are diagnosed with a HER2+ breast cancer below the age of 40 should be conservatively given 0.5 point.** Phenotype points in unrelated probands should be tallied using the simplified table for tallying PS4 proband points._Caveats_: Points attributed to HER2 status may only be applied in unrelated individuals who underwent multigene panel testing; individuals who underwent targeted _TP53_ single gene testing may not count towards applied points.Variant must meet PM2\\_Supporting in order for PS4 to be applied at any strength.\n\nSee simplified table for tallying probing points for PS4",
"label": "PS4",
"ns": "009",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 4-7.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-1.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639222",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639222",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuW---"
},
{
"entContent": {
"_uniqueProp": "009_PP4_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency of likely somatic variants in blood among patients undergoing multigene panel testing is high for variants in _TP53_ (PMID: 29189820). _TP53_ variants observed at a low variant allele fraction (VAF) may be due to true constitutional mosaicism (which can be confirmed by observing the variant in other non-lymphocyte tissues; in the tumor at higher VAF; and/or segregating in other family members); technical assay issues; a clone driven by underlying malignancy or previous treatment with chemotherapy; or clonal hematopoiesis of indeterminate potential (CHIP). \n\nPositive selection has been proposed to be a mechanism driving clonal hematopoiesis (CH). Fortuno et al., 2022 (PMID: 34906512) demonstrated that the observation of _TP53_ variants at low VAF is a significant predictor of variant pathogenicity. Likelihood ratios toward pathogenicity associated with a VAF 5-25% corresponded to the ACMG-AMP strength level of moderate, and supporting with VAF 25-35%. Code-weighting for this rule was derived from datasets that are equivalent to the information available to diagnostic laboratories with the aim that this would be accurate for interpretation for low VAF variants in a real world testing situation. Uncertainty about the variant truly being the result of CHIP is built into the code strengths assigned, which therefore excludes confirmed constitutional mosaicism. _Caveats_: This evidence code assumes a somatic origin of the TP53 variant, and therefore is inconsistent with other phenotype-based criteria, such as PS4, PS2, PP1, and BS2. PP4 and points towards any phenotype-based rule codes cannot be applied _in the same individual_ in combination. PP4 and PS2 cannot be applied together _in the same individual_. Do not apply this code if variant meets BA1 or BS1. Variant must have been detected on MGPT in order for this code to be applied.",
"label": "PP4",
"ns": "009",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "At least 2 independent observations of the variant with VAF 5-25%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Observation of the variant with VAF at or below 35%.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639229",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639229",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuS--_"
},
{
"entContent": {
"_uniqueProp": "009_BP1_nuclear_TP53",
"additionalComments": "This rule code does not apply to these genes, as truncating variants account for only a portion of disease causing variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "009",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639212",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639212",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--I"
},
{
"entContent": {
"_uniqueProp": "009_BP3_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "009",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639218",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639218",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--E"
},
{
"entContent": {
"_uniqueProp": "009_BS1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS1",
"ns": "009",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/16644204/"
}
],
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filtering allele frequency (FAF) of ≥ 0.0003 but \\< 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding subpopulations influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Sub-population must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have an allele balance below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. \n\nIn general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639206",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639206",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpS--R"
},
{
"entContent": {
"_uniqueProp": "009_BS3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This rule should be used and weighted appropriately for variants with functional evidence of loss of function. Follow SVI guidance regarding control numbers for functional studies. _Caveat:_ Do not apply BS3 at any weight for “missense” variants using assays done at the protein level (such as Kato et al. or Giacomelli et al.) if PP3 is applied based on SpliceAI. If there is any laboratory evidence, including RNA-seq data, of splicing aberration for the genetic variant being assessed, for which PVS1\\_Variable Weight (RNA) might be considered instead.\n\n**Data Supporting Functional Classes:**\n\n**Kato et al. 2003 (PMID: 12826609) Transactivation Class:** Classification based on the median transactivation activity using eight promoters in yeast. Values can be found in the NCI TP53 Database.\n\nNon-functional: ≤ 20% activity\n\nPartially-functional: > 20% and ≤ 75% activity\n\nFunctional : > 75% activity (variants showing supertransactivation are treated as Functional)\n\n**Giacomelli et al., 2018 (PMID: 30224644):** Classification based on results from growth suppression assays in A549 human cells.\n\nLOF: Etoposide Z-score ≤ -0.21\n\nNo LOF: Etoposide Z-score > -0.21 \n\n**Kawaguchi et al., 2005 (PMID: 16007150):** Classification based on the ability to form an oligomer in yeast.\n\nAbnormal: Monomer/dimer\n\nNormal: Tetramer\n\n**Other assays:** In vitro growth assays in H1299 human cells from Kotler et al., 2018 (PMID: 29979965) with RFS score ≥ -1.0 for LOF and RFS score \\< -1.0 for noLOF. Or colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, or knock-in mouse models.\n\nNon-systematic assays are harder to calibrate, but if they meet Brnich et al., 2019 (PMID: 31892348) recommendations for the application of functional evidence and they are in agreement with Kato et al., 2003 , they should be taken into account. A large proportion of these assays are documented in the NCI TP53 database and thus can easily be found by curators. Second assays that may be considered include colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models, and growth suppression assays.\n\nSee Functional Flowchart for more information and guidance on application of functional rule codes",
"label": "BS3",
"ns": "009",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Functional on Kato et al. data **AND** no loss of function (LOF) on Giacomelli et al. data **AND/OR** no evidence of LOF on another assay (e.g. Kotler or a second assay)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Partially functional on Kato et al. data **AND** no evidence of loss of function (LOF) on Giacomelli et al. data **AND** no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) **AND** normal or no data on Kawaguchi et al. data. Do not apply BS3\\_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data **AND** no evidence of LOF (or no data available) on Giacomelli et al. data. \n\nBS3\\_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639210",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639210",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxue--A"
},
{
"entContent": {
"_uniqueProp": "009_BS4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS4",
"ns": "009",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639213",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639213",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqC--E"
},
{
"entContent": {
"_uniqueProp": "009_PM6_nuclear_TP53",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": [
"See above for PS2_PM6 combined rule"
],
"label": "PM6",
"ns": "009",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639214",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639214",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxp2--D"
},
{
"entContent": {
"_uniqueProp": "009_BA1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "009",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding subpopulations influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Sub-population must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have an allele balance below 0.35. To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. \n\n In general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639225",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639225",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpS--S"
},
{
"entContent": {
"_uniqueProp": "009_PM5_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "This code can be applied for a missense change at an amino acid residue where one or more pathogenic/likely pathogenic variants have been identified. The other variant must be interpreted as pathogenic or likely pathogenic following the ClinGen _TP53_ VCEP’s specifications. The previously established pathogenic/likely pathogenic variant must reach a classification of pathogenicity without PM5. Caveats: If both PS1 and PM5 are met, apply the strongest weight possible for each rule code not to exceed a combined strength of strong (4 points in total).\n\nGrantham should be used to compare the variants. The variant being evaluated must be equal or worse (value is greather than) than the known pathogenic variant (i.e. the variant residue should be equally chemically different or more chemically different than the known pathogenic residue in comparison to the wild type residue). Splicing should be ruled out with either RNA data or SpliceAI (SpliceAI \\< 0.2).",
"label": "PM5",
"ns": "009",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the _TP53_ VCEP’s specifications have been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the _TP53_ VCEP’s specifications has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the _TP53_ VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5\\_Supporting code application.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639211",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639211",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqe--C"
},
{
"entContent": {
"_uniqueProp": "009_PM2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM2",
"ns": "009",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be \\<0.00004 (0.004%). Subpopulations influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1), curators should recalculate the total allele frequency based on the number of alleles between 0.35-0.65 to assess whether PM2 may be met after excluding the low AB alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database.\n\nIn general, the most recent version of gnomAD with a non-cancer dataset should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if there is a reason to believe they would provide superior information for a particular variant type or have a large sample size, or better representation for certain subpopulations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639231",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639231",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxuW--_"
},
{
"entContent": {
"_uniqueProp": "009_BS2_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in _TP53_ carriers vs. TP53-negative controls. Of note, in the internal data the proportion of individuals with sarcoma diagnosed ≥ age 61 was higher in carriers (0.60%) than in non-carriers (0.12%) and was a significant predictor of pathogenicity when included in the model. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al, 2018 (PMID: 29300386), our most conservative results support the following rules application. Females counted towards BS2 should be unrelated probands. If there is any variant allele frequency (VAF) provided, variants with VAF ≤ 35%, suggestive of somatic origin, should not be included in these counts.",
"label": "BS2",
"ns": "009",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639208",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639208",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqW--_"
},
{
"entContent": {
"_uniqueProp": "009_PM4_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "009",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639209",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639209",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpS--U"
},
{
"entContent": {
"_uniqueProp": "009_PS3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Kato et al., 2003 (PMID: 12826609) systematic data performed best on our test set of reference variants. These data thus remain the primary functional assay underlying the classification. Giacomelli et al., 2018 (PMID: 30224644) assays are also systematic and are available for all p53 missense variants. When using cut-offs derived from original publication data (optimal cut-offs separating silent and common cancer variants), they show good concordance with other assays. Giacomelli LOF class can thus be used to support and complement Kato data. If Kato data is supported by Kawaguchi et al., 2005 (PMID: 16007150) in the tetramerization domain and tetramerization is affected, this can be used to apply PS3\\_Supporting. Kotler et al., 2018 (PMID: 29979965) data are available for a large number of variants with different effects, but only for those within the DNA binding domain. They may be used as an additional non-systematic missense LOF assay or for small deletions. _Caveat:_ Do not apply PS3 at any weight for “missense” variants using assays done at the protein level (such as Kato et al. or Giacomelli et al.) if PP3 is applied based on SpliceAI. If there is any laboratory evidence, including RNA-seq data, of splicing aberration for the genetic variant being assessed, for which PVS1\\_Variable Weight (RNA) might be considered instead.\n\n**Data Supporting Functional Classes:**\n\n**Kato et al. 2003 (PMID: 12826609) Transactivation Class:** Classification based on the median transactivation activity using eight promoters in yeast. Values can be found in the NCI TP53 Database.\n\nNon-functional: ≤ 20% activity\n\nPartially-functional: > 20% and ≤ 75% activity\n\nFunctional : > 75% activity (variants showing supertransactivation are treated as Functional)\n\n**Giacomelli et al., 2018 (PMID: 30224644):** Classification based on results from growth suppression assays in A549 human cells.\n\nLOF: Etoposide Z-score ≤ -0.21\n\nNo LOF: Etoposide Z-score > -0.21\n\n**Kawaguchi et al., 2005 (PMID: 16007150):** Classification based on the ability to form an oligomer in yeast.\n\nAbnormal: Monomer/dimer\n\nNormal: Tetramer\n\n**Other assays:** In vitro growth assays in H1299 human cells from Kotler et al., 2018 (PMID: 29979965) with RFS score ≥ -1.0 for LOF and RFS score \\< -1.0 for noLOF. Or colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, or knock-in mouse models.\n\nNon-systematic assays are harder to calibrate, but if they meet Brnich et al., 2019 (PMID: 31892348) recommendations for the application of functional evidence and they are in agreement with Kato et al., 2003 , they should be taken into account. A large proportion of these assays are documented in the NCI TP53 database and thus can easily be found by curators. Second assays that may be considered include colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models, and growth suppression assays.\n\nThis rule should be used and weighted appropriately for variants with functional evidence of loss of function. Follow SVI guidance regarding control numbers for functional studies. Downgrade to PS3\\_Moderate if PVS1\\_Strong is applied. Do not apply PS3 at any strength if PVS1 is applied at full strength.\n\nSee Functional Flowchart for more information and guidance on application of functional rule codes",
"label": "PS3",
"ns": "009",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Non-functional on Kato et al. data **AND** loss of function (LOF) on Giacomelli et al. data **AND/OR** LOF on another assay (e.g. Kotler or a second assay showing low function)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Partially functional on Kato et al. data **AND** loss of function (LOF) on Giacomelli et al. data **AND/OR** LOF on another assay (e.g. Kotler or a second assay showing low function). Do not apply PS3\\_Moderate if any assay evidence is conflicting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Non-functional on Kato et.al data **AND** abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data **AND** LOF (or no data available) on Giacomelli et al. data.\n\nPS3\\_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639219",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639219",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--G"
},
{
"entContent": {
"_uniqueProp": "009_BP4_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "According to the published study by Fortuno et al., 2018 (PMID: 29775997) comparing the performance of different bioinformatics tools for _TP53_, the tools selected are aGVGD (not available for single amino acid inframe deletions) and BayesDel. To investigate potential effects on splicing for intronic, silent, and apparent missense variants, the SpliceAI tool was selected based on recommendations from the ClinGen SVI Splicing Subgroup. All variants should be assessed to consider if there are splicing effects predicted.\n\n**Missense Variants** _(See Flowchart for application of PP3 and BP4 rule codes for missense variants):_\n\n**BP4\\_Moderate:** BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4\\_Moderate) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**BP4:** BayesDel \\< 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**Single amino acid inframe deletions** (_See single aa BayesDel spreadsheet):_\n\n**BP4**: BayesDel score \\< 0.16 AND no predicted splicing impact (Splice AI \\< 0.2)\n\n**Silent or Intronic Variants (outside ± 1,2 positions):**\n\n**BP4:** SpliceAI ≤ 0.1",
"label": "BP4",
"ns": "009",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29775997/"
}
],
"sepioID": "SEPIO-CG:99046",
"specificationType": [
"gene-specific"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4\\_Moderate) AND no predicted differences in splicing (SpliceAI \\< 0.2)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants):_\n\nBayesDel \\< 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI \\< 0.2)\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet):_\n\nBayesDel score \\< 0.16 AND no predicted splicing impact (Splice AI \\< 0.2)\n\n**Silent or Intronic Variants (outside ± 1,2 positions):**\n\nSpliceAI ≤ 0.1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639220",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639220",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpS--T"
},
{
"entContent": {
"_uniqueProp": "009_PP1_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "Meioses should be counted for individuals who both carry the variant and have a relevant cancer (see LFS cancers table). Meioses can be counted through unaffected obligate carriers. Caution should be used in counting meioses across many families where breast cancer is the only cancer present as this is a common cancer type. It is preferable that breast cancer predisposition syndromes have been ruled out with genetic testing, but this is not required to apply meioses.\n\nIn cases where multiple individuals in a family have a relevant cancer and only tumor testing demonstrating the variant (no germline data), meioses may be applied if the variant has been demonstrated in the germline in at least one individual in the family. (Caveat: Positive tumor testing must exist in multiple family members; meioses should not be applied if there is only positive tumor testing in a single individual. If the variant allele fraction in the tumor is not consistent with the variant being heterozygous it should not count towards meioses. Use caution if the family does not meet Classic LFS criteria). \n\nDo not apply PP1 if variant meets BA1/BS1 criteria.\n\nSee Table of LFS cancers for PP1 (and PS2) code application.",
"label": "PP1",
"ns": "009",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Cosegregation must be observed in ≥ 7 meioses across > 1 family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Cosegregation must be observed in 5-6 meioses in/across 1 or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Cosegregation must be observed in 3-4 meioses in/across 1 or more families",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639221",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639221",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxpu--F"
},
{
"entContent": {
"_uniqueProp": "009_BP5_nuclear_TP53",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "009",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639224",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639224",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqS--H"
},
{
"entContent": {
"_uniqueProp": "009_PP3_nuclear_TP53",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "According to the published study by Fortuno et al., 2018 (PMID: 29775997) comparing the performance of different bioinformatics tools for _TP53_, the tools selected are aGVGD (not available for single amino acid inframe deletions) and BayesDel. To investigate potential effects on splicing for intronic, silent, and apparent missense variants, the SpliceAI tool was selected based on recommendations from the ClinGen SVI Splicing Subgroup. All variants should be assessed to consider if there are splicing effects predicted. PP3 should not be used in combination with PVS1.\n\n**Missense variants** _(See Flowchart for application of PP3 and BP4 rule codes for missense variants)_\n\n* **PP3\\_Moderate:** aGVGD Class C65 and BayesDel score ≥ 0.16\n* **PP3:** aGVGD class C25-C55 and BayesDel score ≥ 0.16\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet)_\n\n* **PP3**: BayesDel score ≥ 0.16\n\n**Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):**\n\n* **PP3:** SpliceAI ≥ 0.2",
"label": "PP3",
"ns": "009",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29775997/"
}
],
"sepioID": "SEPIO-CG:99035",
"specificationType": [
"gene-specific",
"strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD Class C65 and BayesDel score ≥ 0.16",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Missense variants** _(See flowchart for application of PP3 and BP4 rules for missense variants)_\n\naGVGD class C25-C55 and BayesDel score ≥ 0.16\n\n**Single amino acid inframe deletions** _(See single aa BayesDel spreadsheet)_\n\nBayesDel score ≥ 0.16\n\n**Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):**\n\nSpliceAI ≥ 0.2",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639227",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639227",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxqe--D"
},
{
"entContent": {
"_uniqueProp": "009_BP6_nuclear_TP53",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TP53"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "009",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638432994",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638432994",
"modified": "2024-03-28T18:26:04.568Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHxp2--C"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018875",
"lbl": "Li-Fraumeni syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6260"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9178"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/li_fraumeni_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/li_fraumeni_syndrome_1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10066795"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1968061860"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/88399"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D016864"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/428850001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0085390"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0111503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3012"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C3476"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_524"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/151623"
}
],
"definition": {
"val": "An autosomal dominant cancer predisposition disorder caused by pathogenic variants in the TP53 gene, characterized by an increased risk of a wide range of cancers, including but not limited to breast cancer, soft tissue sarcomas, osteosarcomas, brain tumors, adrenocortical carcinoma and leukemias.",
"xrefs": [
"Orphanet:524",
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "LFS",
"xrefs": [
"DOID:3012",
"OMIM:151623"
]
},
{
"pred": "hasExactSynonym",
"val": "Li Fraumeni syndrome",
"xrefs": [
"GARD:0006902"
]
},
{
"pred": "hasExactSynonym",
"val": "Li-Fraumeni familial cancer susceptibility syndrome",
"xrefs": [
"NCIT:C3476"
]
},
{
"pred": "hasExactSynonym",
"val": "Li-Fraumeni familiar cancer susceptibility syndrome",
"xrefs": [
"DOID:3012"
]
},
{
"pred": "hasExactSynonym",
"val": "Li-Fraumeni syndrome",
"xrefs": [
"DOID:3012",
"NCIT:C3476",
"OMIM:151623",
"Orphanet:524",
"icd11.foundation:1968061860"
]
},
{
"pred": "hasExactSynonym",
"val": "Li-Fraumeni syndrome caused by mutation in TP53",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "SBLA syndrome",
"xrefs": [
"DOID:3012",
"OMIM:151623"
]
},
{
"pred": "hasExactSynonym",
"val": "TP53 Li-Fraumeni syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "TP53-related Li-Fraumeni syndrome",
"xrefs": [
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "sarcoma, breast, leukaemia and adrenal gland syndrome",
"xrefs": [
"DOID:3012"
]
},
{
"pred": "hasExactSynonym",
"val": "sarcoma, breast, leukemia and adrenal gland syndrome"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "LFS1",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "LFS3",
"xrefs": [
"MONDO:0012234",
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Li-Fraumeni-like syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "SBLA syndrome (sarcoma, breast, leukemia, and adrenal gland)",
"xrefs": [
"GARD:0006902"
]
},
{
"pred": "hasRelatedSynonym",
"val": "sarcoma family syndrome of 51 and Fraumeni"
},
{
"pred": "hasRelatedSynonym",
"val": "sarcoma family syndrome of Li and Fraumeni",
"xrefs": [
"GARD:0006902"
]
}
],
"xrefs": [
{
"val": "DOID:0111503"
},
{
"val": "DOID:3012"
},
{
"val": "GARD:6902"
},
{
"val": "ICD9:V84.01"
},
{
"val": "MEDGEN:88399"
},
{
"val": "MESH:D016864"
},
{
"val": "MedDRA:10066795"
},
{
"val": "NCIT:C3476"
},
{
"val": "NORD:1913"
},
{
"val": "OMIM:151623"
},
{
"val": "OMIM:609266"
},
{
"val": "Orphanet:524"
},
{
"val": "SCTID:428850001"
},
{
"val": "UMLS:C0085390"
},
{
"val": "icd11.foundation:1968061860"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018875",
"name": "Li-Fraumeni syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0018875",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018875",
"entType": "Disease",
"ldhId": "135642164",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642164",
"modified": "2025-10-07T15:46:33.874Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YVCu---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056965451219000,
"agr": "HGNC:11998",
"alias_name": [
"Li-Fraumeni syndrome"
],
"alias_symbol": [
"p53",
"LFS1"
],
"ccds_id": [
"CCDS73969",
"CCDS73970",
"CCDS73971",
"CCDS11118",
"CCDS45605",
"CCDS45606",
"CCDS73963",
"CCDS73964",
"CCDS73965",
"CCDS73966",
"CCDS73967",
"CCDS73968"
],
"cosmic": "TP53",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2008-01-16",
"ena": [
"AF307851"
],
"ensembl_gene_id": "ENSG00000141510",
"entrez_id": "7157",
"hgnc_id": "HGNC:11998",
"location": "17p13.1",
"location_sortable": "17p13.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"IARC TP53 Mutation Database|http://www-p53.iarc.fr/",
"p53 UMD TP53 mutation database|http://p53.fr/",
"Database of Germline p53 Mutations|http://www.lf2.cuni.cz/projects/germline_mut_p53.htm",
"MUTP53LOAD, Mutant p53 Loss Of Activity Database|http://www.umd.be:2072/",
"LRG_321|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_321.xml"
],
"mane_select": [
"ENST00000269305.9",
"NM_000546.6"
],
"mgd_id": [
"MGI:98834"
],
"name": "tumor protein p53",
"omim_id": [
"191170"
],
"orphanet": 120204,
"pubmed_id": [
6396087,
3456488,
2047879
],
"refseq_accession": [
"NM_000546"
],
"rgd_id": [
"RGD:3889"
],
"status": "Approved",
"symbol": "TP53",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc060aur.1",
"uniprot_ids": [
"P04637"
],
"uuid": "0c950245-0803-451c-bea6-172d7187ef53",
"vega_id": "OTTHUMG00000162125"
},
"NCBI": {
"id": "7157"
}
},
"entId": "TP53",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11998",
"entType": "Gene",
"ldhId": "135641899",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641899",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "009_nuclear_TP53",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0018875",
"preferredTitle": "Li-Fraumeni syndrome"
}
],
"gene": "TP53",
"preferredTranscript": "NM_000546.4"
}
],
"ns": "009",
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "135640873",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640873",
"modified": "2024-03-28T18:26:04.465Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_h6SHyTO--H"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approvalDate": "2017-08-10T00:00:00.000Z",
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2019-08-07T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "TP53",
"shortBaseName": "TP53",
"shortTitle": "TP53 VCEP",
"title": "TP53 Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50013",
"entIri": "http://clinicalgenome.org/affiliation/50013",
"entType": "Organization",
"ldhId": "135637637",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637637",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--D"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637581",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637581",
"modified": "2024-08-08T17:58:03.250Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_iRKi-Oq---"
},
{
"entContent": {
"approvedOn": "2021-06-02T00:00:00.000Z",
"description": "LSD EP specifications to the ACMG/AMP Variant Curation Guidelines",
"namespace": "GN010",
"notes": "",
"references": [],
"releaseNotes": "\n * Specifications for PS3 and BS3 have been revised and the strength has been downgraded.\n * PM2 has been downgraded to PM2_Supporting.\n * PP4 has been revised to allow the use of additional evidence types with strength of evidence based on a points system.\n * Cases are no longer required to meet the strict PP4 criterion in order to be counted for PM3.\n * Specifications for PM1 and BS2 are now included.\n * The tools used for in silico prediction of the impact of splice variants and in frame insertions and deletions for PP3 and BP4 have been revised.",
"shortTitle": "LSD VCEP ACMG/AMP Specifications",
"specificationSource": "https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-06-02T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"010"
],
"title": "ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0"
},
"entId": "GN010",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "010_PP3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "010",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PP3 upgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n * REVEL score >0.7 for missense variants.\n * In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel).\n * Predicted impact on splicing by SpliceAI (score >0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639308",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639308",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--I"
},
{
"entContent": {
"_uniqueProp": "010_BP4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "010",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product.\n * REVEL score <0.5 for missense variants.\n * In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel.\n * No predicted impact on splicing by SpliceAI (score <0.2)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639301",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639301",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--B"
},
{
"entContent": {
"_uniqueProp": "010_PS3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "010",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/18425781"
},
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/22644586"
}
],
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * <5% wild type GAA activity when the variant is expressed in a heterologous cell type and evidence of abnormal GAA synthesis and/or processing.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n * <30% wild type GAA activity when the variant is expressed in a heterologous cell type.\n * RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639300",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639300",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--A"
},
{
"entContent": {
"_uniqueProp": "010_BP2_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Allelic Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "010",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639297",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639297",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--_"
},
{
"entContent": {
"_uniqueProp": "010_PM6_nuclear_GAA",
"additionalComments": "See explanation for PS2.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "De novo Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "010",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639295",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639295",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--b"
},
{
"entContent": {
"_uniqueProp": "010_BS3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "010",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function.\n * >60% normal GAA activity when the variant is expressed in a heterologous cell type.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n * >50% activity when the variant is expressed in a heterologous cell type, or >30% activity if there is also evidence of normal synthesis and processing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639291",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639291",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--H"
},
{
"entContent": {
"_uniqueProp": "010_BS1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "010",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease.\n * Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639287",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639287",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi---"
},
{
"entContent": {
"_uniqueProp": "010_PP5_nuclear_GAA",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAA"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "010",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433025",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433025",
"modified": "2022-01-19T20:31:31.320Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--L"
},
{
"entContent": {
"_uniqueProp": "010_BP6_nuclear_GAA",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAA"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "010",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433024",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433024",
"modified": "2022-01-19T20:31:31.320Z",
"modifier": "genbadmin",
"rev": "_h6SHxou---"
},
{
"entContent": {
"_uniqueProp": "010_BP7_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "010",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639309",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639309",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--C"
},
{
"entContent": {
"_uniqueProp": "010_BP5_nuclear_GAA",
"additionalComments": "* An individual could be a carrier of a pathogenic variant in GAA and have another disorder.\n* There is no known alternate molecular basis for deficiency of GAA activity, other than variants in GAA.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Other Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "010",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639305",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639305",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--_"
},
{
"entContent": {
"_uniqueProp": "010_PS1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "010",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639296",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639296",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--I"
},
{
"entContent": {
"_uniqueProp": "010_BP1_nuclear_GAA",
"additionalComments": "Does not apply. All types of variants cause Pompe disease.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "010",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639293",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639293",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--G"
},
{
"entContent": {
"_uniqueProp": "010_BS2_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "010",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult.\n * Homozygous individual of any age with normal GAA activity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639289",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639289",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--J"
},
{
"entContent": {
"_uniqueProp": "010_PM1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "010",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.\n * Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA:- D282, W376, D404, L405, I441, W481, W516, D518, M519, R600, W613, D616, W618, F649, L650, H674.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639311",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639311",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--C"
},
{
"entContent": {
"_uniqueProp": "010_BP3_nuclear_GAA",
"additionalComments": "There are no known repetitive regions without known function in GAA.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "010",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639299",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639299",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--J"
},
{
"entContent": {
"_uniqueProp": "010_BS4_nuclear_GAA",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Segregation Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "010",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0071",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639294",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639294",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--H"
},
{
"entContent": {
"_uniqueProp": "010_PM5_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "010",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be 'likely pathogenic' has been seen before.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639292",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639292",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--H"
},
{
"entContent": {
"_uniqueProp": "010_PM4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "010",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of two or more amino acids but less than one exon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.\n * In frame deletion/insertions of one amino acid.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639290",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639290",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--_"
},
{
"entContent": {
"_uniqueProp": "010_PM3_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Allelic Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "010",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Detected in trans with a pathogenic variant. Points-based system. See main specifications document.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639288",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639288",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--I"
},
{
"entContent": {
"_uniqueProp": "010_PM2_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "010",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Low frequency in population databases.\n * Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639312",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639312",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--M"
},
{
"entContent": {
"_uniqueProp": "010_BA1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "010",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Common in population databases.\n * Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639306",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639306",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--B"
},
{
"entContent": {
"_uniqueProp": "010_PVS1_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "010",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/1856189/"
}
],
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA.\n * Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916.\n * In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9).\n * Initiator codon variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n * Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay.\n * Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639304",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639304",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--K"
},
{
"entContent": {
"_uniqueProp": "010_PS4_nuclear_GAA",
"additionalComments": "There are no case-control studies for Pompe disease. As this is a recessive disorder, the prevalence of the variant in affected individuals may not be increased compared to controls (who could be heterozygous carriers). The number of patients with the variant will be addressed by the PM3 evidence code.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Population Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "010",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639303",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639303",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi---"
},
{
"entContent": {
"_uniqueProp": "010_PP1_nuclear_GAA",
"additionalComments": "Sib-ships large enough to meet this criterion are extremely rare. In addition, because GAA is the only gene involved in Pompe disease, all patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Segregation Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "010",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0060",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639302",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639302",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--_"
},
{
"entContent": {
"_uniqueProp": "010_PS2_nuclear_GAA",
"additionalComments": "De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "De novo Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "010",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0051",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639298",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639298",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--I"
},
{
"entContent": {
"_uniqueProp": "010_PP4_nuclear_GAA",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Other Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "010",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n * Points-based system. See main specifications document",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639310",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639310",
"modified": "2021-11-05T21:07:12.738Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--L"
},
{
"entContent": {
"_uniqueProp": "010_PP2_nuclear_GAA",
"additionalComments": "Does not apply; there are benign and pathogenic missense variants in GAA.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0009290"
],
"evidenceCategory": "Functional Data",
"gene": [
"GAA"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "010",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639307",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639307",
"modified": "2022-01-19T20:33:34.305Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--K"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009290",
"lbl": "glycogen storage disease II",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009290"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/pompe_disease"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10053185"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/5340"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/274864009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0017921"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/E74.02"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_2752"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84734"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_365"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/232300"
}
],
"definition": {
"val": "Glycogen storage disease due to acid maltase deficiency (AMD) is an autosomal recessive trait leading to metabolic myopathy that affects cardiac and respiratory muscles in addition to skeletal muscle and other tissues. AMD represents a wide spectrum of clinical presentations caused by an accumulation of glycogen in lysosomes: Glycogen storage disease due to acid maltase deficiency, infantile onset, non-classic infantile onset and adult onset. Early onset forms are more severe and often fatal.",
"xrefs": [
"Orphanet:365"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Alpha-1,4-glucosidase acid deficiency",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "GAA glycogen storage disease",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "GSD due to acid maltase deficiency",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "GSD type 2",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "GSD type II",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "Pompe Disease",
"xrefs": [
"NORD:1595",
"OMIM:232300",
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "Pompe disease",
"xrefs": [
"OMIM:232300",
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "Pompe's disease",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"val": "acid maltase deficiency",
"xrefs": [
"DOID:2752",
"OMIM:232300"
]
},
{
"pred": "hasExactSynonym",
"val": "deficiency of glucoamylase",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"val": "deficiency of maltase",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "generalised glycogenosis"
},
{
"pred": "hasExactSynonym",
"val": "generalized glycogenosis",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogen storage disease II",
"xrefs": [
"DOID:2752",
"MONDO:Lexical"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogen storage disease caused by mutation in GAA",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogen storage disease type 2",
"xrefs": [
"MONDORULE:1",
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogen storage disease type II",
"xrefs": [
"DOID:2752",
"MONDORULE:3",
"NCIT:C84734",
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogen storage disease, type II",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogenosis due to acid maltase deficiency",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogenosis type 2",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogenosis type II",
"xrefs": [
"Orphanet:365"
]
},
{
"pred": "hasExactSynonym",
"val": "glycogenosis, type 2",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasExactSynonym",
"val": "lysosomal alpha-1,4-glucosidase deficiency",
"xrefs": [
"DOID:2752"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Aglucosidase alfa",
"xrefs": [
"GARD:0005714"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Alpha-1,4-glucosidase deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "Cardiomegalia Glycogenica diffusa"
},
{
"pred": "hasRelatedSynonym",
"val": "GAA deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "GSD 2"
},
{
"pred": "hasRelatedSynonym",
"val": "GSD II",
"xrefs": [
"GARD:0005714"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "GSD2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "acid maltase deficiency disease",
"xrefs": [
"GARD:0005714"
]
},
{
"pred": "hasRelatedSynonym",
"val": "deficiency of alpha-glucosidase",
"xrefs": [
"GARD:0005714"
]
},
{
"pred": "hasRelatedSynonym",
"val": "deficiency of lysosomal alpha-glucosidase",
"xrefs": [
"GARD:0005714"
]
},
{
"pred": "hasRelatedSynonym",
"val": "glucosidase acid-1,4-alpha deficiency",
"xrefs": [
"GARD:0002503"
]
},
{
"pred": "hasRelatedSynonym",
"val": "glycogen storage disease 2"
},
{
"pred": "hasRelatedSynonym",
"val": "glycogen storage disease due to acid maltase deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "glycogenosis, generalized, Cardiac form"
}
],
"xrefs": [
{
"val": "DOID:2752"
},
{
"val": "GARD:5714"
},
{
"val": "ICD10CM:E74.02"
},
{
"val": "MEDGEN:5340"
},
{
"val": "MedDRA:10053185"
},
{
"val": "NANDO:1200138"
},
{
"val": "NANDO:1200825"
},
{
"val": "NANDO:2200569"
},
{
"val": "NCIT:C84734"
},
{
"val": "NORD:1595"
},
{
"val": "OMIM:232300"
},
{
"val": "Orphanet:365"
},
{
"val": "SCTID:274864009"
},
{
"val": "UMLS:C0017921"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009290",
"name": "glycogen storage disease II",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0009290",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009290",
"entType": "Disease",
"ldhId": "135642171",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642171",
"modified": "2025-10-07T15:43:53.305Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V4SW---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948116160500,
"agr": "HGNC:4065",
"alias_name": [
"Pompe disease",
"glycogen storage disease type II"
],
"ccds_id": [
"CCDS32760"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-04-13",
"date_name_changed": "2020-11-10",
"ensembl_gene_id": "ENSG00000171298",
"entrez_id": "2548",
"enzyme_id": [
"3.2.1.20"
],
"gene_group": [
"Glycoside hydrolase family 31"
],
"gene_group_id": [
1413
],
"hgnc_id": "HGNC:4065",
"iuphar": "objectId:2611",
"location": "17q25.3",
"location_sortable": "17q25.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"GAA - Pompe disease (glycogen storage disease type II)|http://www.LOVD.nl/GAA",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GAA",
"LRG_673|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_673.xml"
],
"mane_select": [
"ENST00000302262.8",
"NM_000152.5"
],
"mgd_id": [
"MGI:95609"
],
"name": "alpha glucosidase",
"omim_id": [
"606800"
],
"orphanet": 121987,
"prev_name": [
"glucosidase, alpha; acid",
"glucosidase alpha, acid"
],
"refseq_accession": [
"NM_000152"
],
"rgd_id": [
"RGD:735227"
],
"status": "Approved",
"symbol": "GAA",
"ucsc_id": "uc002jxo.4",
"uniprot_ids": [
"P10253"
],
"uuid": "75d9f82c-beed-42e4-98c0-218cf37cf43c",
"vega_id": "OTTHUMG00000177537"
},
"NCBI": {
"id": "2548"
}
},
"entId": "GAA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4065",
"entType": "Gene",
"ldhId": "135641911",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641911",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyAy--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "010_nuclear_GAA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0009290",
"preferredTitle": "glycogen storage disease II"
}
],
"gene": "GAA",
"preferredTranscript": "NM_000152.4"
}
],
"ns": "010"
},
"entType": "RuleSet",
"ldhId": "135640933",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640933",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--A"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-09-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2019-08-21T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2019-08-21T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Lysosomal Diseases",
"shortBaseName": "LSD",
"shortTitle": "Lysosomal Diseases VCEP",
"title": "Lysosomal Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50009",
"entIri": "http://clinicalgenome.org/affiliation/50009",
"entType": "Organization",
"ldhId": "135637633",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637633",
"modified": "2023-04-27T19:13:01.752Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEC--b"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637582",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637582",
"modified": "2023-09-29T15:16:46.069Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--I"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"description": "This version specified for the following genes: ITGA2B, ITGB3",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN011",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"011"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1",
"version": "2.1.0"
},
"entId": "GN011",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "011_BP6_nuclear_ITGA2B_ITGB3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ITGA2B",
"ITGB3"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "011",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433054",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433054",
"modified": "2022-01-19T20:31:31.552Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--N"
},
{
"entContent": {
"_uniqueProp": "011_PVS1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "011",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PVS1 downgraded in strength to Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "PVS1 downgraded in strength to Moderate",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639385",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639385",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--H"
},
{
"entContent": {
"_uniqueProp": "011_PS2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "De novo Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "011",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639379",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639379",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--F"
},
{
"entContent": {
"_uniqueProp": "011_BS3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "011",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Must demonstrate normal aggregometry in a transgenic mouse model.\n OR\n* In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639372",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639372",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--N"
},
{
"entContent": {
"_uniqueProp": "011_PM3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "011",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639369",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639369",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--_"
},
{
"entContent": {
"_uniqueProp": "011_BP5_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Other Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "011",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639386",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639386",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--F"
},
{
"entContent": {
"_uniqueProp": "011_PP1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Segregation Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "011",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregations in proband plus >2 affected relatives.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in proband plus 2 affected relatives.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in proband plus 1 affected relative.\n * Affected relatives must have both variants identified in proband.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639383",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639383",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--_"
},
{
"entContent": {
"_uniqueProp": "011_BP4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "011",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "REVEL score of < 0.25",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639382",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639382",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--E"
},
{
"entContent": {
"_uniqueProp": "011_BP1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "011",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639374",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639374",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--A"
},
{
"entContent": {
"_uniqueProp": "011_PP5_nuclear_ITGA2B_ITGB3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ITGA2B",
"ITGB3"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "011",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433055",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433055",
"modified": "2022-01-19T20:31:31.552Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--H"
},
{
"entContent": {
"_uniqueProp": "011_PP3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "011",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score of ≥ 0.7\n OR\n>2 independent in silico missense predictors predict a damaging impact",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639389",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639389",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--G"
},
{
"entContent": {
"_uniqueProp": "011_PP2_nuclear_ITGA2B_ITGB3",
"additionalComments": "This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233).",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "011",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This rule does not apply because benign missense variants are not rare.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639388",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639388",
"modified": "2022-01-19T20:33:34.409Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--A"
},
{
"entContent": {
"_uniqueProp": "011_BA1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "011",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639387",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639387",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--I"
},
{
"entContent": {
"_uniqueProp": "011_PM6_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "De novo Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "011",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations.\n* Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations.\n * Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639376",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639376",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--E"
},
{
"entContent": {
"_uniqueProp": "011_PM5_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "011",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use at adjusted strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639373",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639373",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--O"
},
{
"entContent": {
"_uniqueProp": "011_BS1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "011",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639368",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639368",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--D"
},
{
"entContent": {
"_uniqueProp": "011_PM2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "011",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Prevalence <1/10,000 (<0.0001) alleles in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639393",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639393",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--_"
},
{
"entContent": {
"_uniqueProp": "011_PM1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "011",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Rule does not apply due to genes being highly polymorphic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639392",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639392",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--F"
},
{
"entContent": {
"_uniqueProp": "011_BP7_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "011",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639390",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639390",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--A"
},
{
"entContent": {
"_uniqueProp": "011_PS4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "011",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Rule does not apply due to rarity of disorder and lack of appropriate studies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639384",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639384",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--G"
},
{
"entContent": {
"_uniqueProp": "011_BP2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "011",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639378",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639378",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--C"
},
{
"entContent": {
"_uniqueProp": "011_PP4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Other Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "011",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patients phenotype or family history is highly specific for a disease with a single genetic etiology",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639391",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639391",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2---"
},
{
"entContent": {
"_uniqueProp": "011_PS3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Functional Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "011",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In a transgenic animal model, must demonstrate minimal to no function.\n OR\n* In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In a model organism or heterologous cell line, significantly reduced surface protein expression (5\n * 25%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS3 downgraded in strength to Supporting",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639381",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639381",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe---"
},
{
"entContent": {
"_uniqueProp": "011_BP3_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "011",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use with no specification",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639380",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639380",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--D"
},
{
"entContent": {
"_uniqueProp": "011_PS1_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "011",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639377",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639377",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--E"
},
{
"entContent": {
"_uniqueProp": "011_BS4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Segregation Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "011",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant not detected in an affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639375",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639375",
"modified": "2021-11-05T21:11:44.829Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--B"
},
{
"entContent": {
"_uniqueProp": "011_PM4_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "011",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639371",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639371",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--b"
},
{
"entContent": {
"_uniqueProp": "011_BS2_nuclear_ITGA2B_ITGB3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100326"
],
"evidenceCategory": "Population Data",
"gene": [
"ITGA2B",
"ITGB3"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "011",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">1 homozygote who is unaffected proven with at least aggregometry.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639370",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639370",
"modified": "2021-11-05T21:11:44.828Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--a"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100326",
"lbl": "Glanzmann thrombasthenia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100326"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1927726560"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/52736"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0040015"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_849"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS273800"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Glanzmann thrombasthenia",
"xrefs": [
"OMIMPS:273800",
"Orphanet:849",
"icd11.foundation:1927726560"
]
}
],
"xrefs": [
{
"val": "GARD:2478"
},
{
"val": "MEDGEN:52736"
},
{
"val": "NORD:1186"
},
{
"val": "OMIMPS:273800"
},
{
"val": "Orphanet:849"
},
{
"val": "UMLS:C0040015"
},
{
"val": "icd11.foundation:1927726560"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100326",
"name": "Glanzmann thrombasthenia"
},
"entId": "MONDO:0100326",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100326",
"entType": "Disease",
"ldhId": "467880243",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880243",
"modified": "2025-10-07T15:48:32.901Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aJUy---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010119",
"lbl": "obsolete Glanzmann's thrombasthenia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0100001",
"val": "MONDO:0031332"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/IAO_0000229"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/2940"
}
],
"deprecated": true
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010119",
"name": "obsolete Glanzmann's thrombasthenia"
},
"entId": "MONDO:0010119",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010119",
"entType": "Disease",
"ldhId": "135642179",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642179",
"modified": "2023-01-27T21:42:10.706Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHysK--B"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010119",
"lbl": "obsolete Glanzmann's thrombasthenia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/IAO_0000229"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/2940"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0100001",
"val": "http://purl.obolibrary.org/obo/MONDO_0031332"
}
],
"deprecated": true,
"xrefs": [
{
"val": "NANDO:2200657"
},
{
"val": "NANDO:2200664"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010119",
"name": "obsolete Glanzmann's thrombasthenia"
},
"entId": "MONDO:0010119",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010119",
"entType": "Disease",
"ldhId": "135642178",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642178",
"modified": "2025-10-07T15:44:07.088Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WFei---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056950432465000,
"agr": "HGNC:6156",
"alias_name": [
"platelet glycoprotein IIIa",
"antigen CD61"
],
"alias_symbol": [
"CD61",
"GPIIIa"
],
"ccds_id": [
"CCDS11511"
],
"cd": "CD61",
"date_approved_reserved": "1988-06-09",
"date_modified": "2021-04-13",
"date_name_changed": "2015-12-15",
"ensembl_gene_id": "ENSG00000259207",
"entrez_id": "3690",
"gene_group": [
"CD molecules",
"Integrin beta subunits"
],
"gene_group_id": [
471,
1159
],
"hgnc_id": "HGNC:6156",
"iuphar": "objectId:2457",
"location": "17q21.32",
"location_sortable": "17q21.32",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_481|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_481.xml"
],
"mane_select": [
"ENST00000559488.7",
"NM_000212.3"
],
"mgd_id": [
"MGI:96612"
],
"name": "integrin subunit beta 3",
"omim_id": [
"173470"
],
"orphanet": 122704,
"prev_name": [
"integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)"
],
"prev_symbol": [
"GP3A"
],
"pubmed_id": [
2454952
],
"refseq_accession": [
"NM_000212"
],
"rgd_id": [
"RGD:628868"
],
"status": "Approved",
"symbol": "ITGB3",
"ucsc_id": "uc002ilj.4",
"uniprot_ids": [
"P05106"
],
"uuid": "63283e01-3bbf-43c0-b2bf-dd051ab8f4a2",
"vega_id": "OTTHUMG00000171956"
},
"NCBI": {
"id": "3690"
}
},
"entId": "ITGB3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6156",
"entType": "Gene",
"ldhId": "135641919",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641919",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056950415687700,
"agr": "HGNC:6138",
"alias_name": [
"protein phosphatase 1, regulatory subunit 93",
"platelet glycoprotein IIb of IIb/IIIa complex"
],
"alias_symbol": [
"CD41B",
"CD41",
"PPP1R93"
],
"ccds_id": [
"CCDS32665"
],
"cd": "CD41",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-04-13",
"date_name_changed": "2015-12-15",
"ensembl_gene_id": "ENSG00000005961",
"entrez_id": "3674",
"gene_group": [
"CD molecules",
"Protein phosphatase 1 regulatory subunits",
"Integrin alpha subunits"
],
"gene_group_id": [
471,
694,
1160
],
"hgnc_id": "HGNC:6138",
"iuphar": "objectId:2441",
"location": "17q21.31",
"location_sortable": "17q21.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_479|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_479.xml"
],
"mane_select": [
"ENST00000262407.6",
"NM_000419.5"
],
"mgd_id": [
"MGI:96601"
],
"name": "integrin subunit alpha 2b",
"omim_id": [
"607759"
],
"orphanet": 122690,
"prev_name": [
"integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)",
"integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41)"
],
"prev_symbol": [
"GP2B"
],
"refseq_accession": [
"NM_000419"
],
"rgd_id": [
"RGD:1596428"
],
"status": "Approved",
"symbol": "ITGA2B",
"ucsc_id": "uc002igt.2",
"uniprot_ids": [
"P08514"
],
"uuid": "32a1045d-58d4-4bb1-8af8-bf83fcde871c",
"vega_id": "OTTHUMG00000177935"
},
"NCBI": {
"id": "3674"
}
},
"entId": "ITGA2B",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6138",
"entType": "Gene",
"ldhId": "135641918",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641918",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "011_nuclear_ITGA2B_ITGB3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100326",
"preferredTitle": "Glanzmann thrombasthenia"
}
],
"gene": "ITGA2B",
"preferredTranscript": "NM_000419.4"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0100326",
"preferredTitle": "Glanzmann thrombasthenia"
}
],
"gene": "ITGB3",
"preferredTranscript": "NM_000212.2"
}
],
"ns": "011"
},
"entType": "RuleSet",
"ldhId": "135640993",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640993",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--D"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN060",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:09.607Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"060"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGB3 Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN060",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243130",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243130",
"modified": "2022-08-18T19:14:13.243Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--B"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN059",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:05.385Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"059"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGA2B Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN059",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243129",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243129",
"modified": "2022-08-18T19:14:09.167Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--D"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637583",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637583",
"modified": "2023-09-29T15:16:47.242Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--I"
},
{
"entContent": {
"approvedOn": "2022-03-01T00:00:00.000Z",
"description": "This version specified for the following genes: RYR1",
"namespace": "GN012",
"notes": "",
"references": [
{
"source": "BioRxiv",
"url": "https://doi.org/10.1101/2020.11.29.402768"
}
],
"releaseNotes": "\n(1) Revised PS4 such that at all strength levels an individual with two VUS/LP/P variants in RYR1 cannot be considered as supporting pathogenicity of either variant.\n(2) PS1 can be used at level moderate for previously classified likely pathogenic variant at the same codon with the same amino acid change.\n(3) PM5 can be used at level supporting for previously classified likely pathogenic variant at the same codon, different amino acid change.\n(4) PM1 should be downgraded to supporting when either PS1 or PM5 are used.",
"shortTitle": "ACMG variant classification Malignant Hyperthermia",
"specificationSource": "https://clinicalgenome.org/docs/clingen-malignant-hyperthermia-susceptibility-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-for/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"012"
],
"title": "ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2",
"version": "2.0.0"
},
"entId": "GN012",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "012_PM1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "012",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well established functional domain.\n* Residues 1-552 (N-terminal region) and 2,101-2,458 (central region) \n* PM1 should not be applied at a moderate weight with PS1/PM5, see PM1_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Located in a mutational hot spot and/or critical and well established functional domain.\n* Residues 1-552 (N-terminal region) and 2,101-2,458 (central region), if PS1/PM5 applicable then PM1 should be used at supporting \n* Residues 4,631-4,991 (C-terminal region).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639473",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639473",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_h6SHxoq--M"
},
{
"entContent": {
"_uniqueProp": "012_BA1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "012",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Popmax allele frequency >0.0038 (0.38%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639468",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639468",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--D"
},
{
"entContent": {
"_uniqueProp": "012_PP1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Segregation Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "012",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in ≥7 reported meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in 5-6 reported meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in 3-4 reported meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639464",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639464",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--G"
},
{
"entContent": {
"_uniqueProp": "012_BP3_nuclear_RYR1",
"additionalComments": "BP3 is not applicable. RYR1 does not have repetitive regions without known function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "012",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639461",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639461",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--F"
},
{
"entContent": {
"_uniqueProp": "012_PS2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "De novo Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "012",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639460",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639460",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--I"
},
{
"entContent": {
"_uniqueProp": "012_PS1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "012",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change\n * Previously established pathogenic variant must reach a classification of pathogenic without PS1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.\n* Previously established likely pathogenic variant must reach a classification of likely pathogenic without PS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639458",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639458",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_h6SHxo6---"
},
{
"entContent": {
"_uniqueProp": "012_PM5_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "012",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic\n * Previously established pathogenic variant must reach a classification of pathogenicity without PM5\n * Grantham score for alternate pathogenic variant must be less than for variant being assessed",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense variant previously determined to be pathogenic.\n * Previously established likely pathogenic variant can be considered supporting evidence, must reach a classification of likely pathogenic without PM5.\n* Grantham score for alternate likely pathogenic variant must be less than for variant being assessed.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639454",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639454",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_h6SHxpC--G"
},
{
"entContent": {
"_uniqueProp": "012_BS3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "012",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Well-established functional studies show no damaging effect on protein function\n * Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Strength, Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Well-established functional studies show no damaging effect on protein function\n * No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3\n * One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist\n * Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639453",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639453",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--D"
},
{
"entContent": {
"_uniqueProp": "012_BS2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "012",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * Two or more variant positive individuals with a negative IVCT/CHCT test",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.\n * One variant positive individual with a negative IVCT/CHCT test",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639451",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639451",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--C"
},
{
"entContent": {
"_uniqueProp": "012_BP6_nuclear_RYR1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RYR1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "012",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433084",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433084",
"modified": "2022-01-19T20:31:31.799Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--_"
},
{
"entContent": {
"_uniqueProp": "012_PP4_nuclear_RYR1",
"additionalComments": "PP4 is not applicable, variants in CACNA1S also result in MHS.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Other Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "012",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639472",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639472",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--E"
},
{
"entContent": {
"_uniqueProp": "012_PS3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "012",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.\n * Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist\n * Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established functional studies supportive of a damaging effect on protein function\n * Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639462",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639462",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--J"
},
{
"entContent": {
"_uniqueProp": "012_PM3_nuclear_RYR1",
"additionalComments": "PM3 is not applicable. MHS is inherited as an autosomal dominant trait with reduced penetrance.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Allelic Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "012",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639450",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639450",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--B"
},
{
"entContent": {
"_uniqueProp": "012_BP7_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "012",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639471",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639471",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--F"
},
{
"entContent": {
"_uniqueProp": "012_PS4_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "012",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls.\n* ≥7 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\n * For variants with popmax MAF gnomAD >0.00006, an odds ratio of ≥18.7 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\n* For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength",
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared withthe prevalence in controls.\n* 1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.\nFor variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639465",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639465",
"modified": "2022-05-12T15:33:55.804Z",
"modifier": "neethus",
"rev": "_h6SHxoq--L"
},
{
"entContent": {
"_uniqueProp": "012_BP2_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Allelic Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "012",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639459",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639459",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--E"
},
{
"entContent": {
"_uniqueProp": "012_BS1_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "012",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Popmax allele frequency >0.0008 (0.08%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639449",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639449",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--H"
},
{
"entContent": {
"_uniqueProp": "012_PM2_nuclear_RYR1",
"additionalComments": "PM2 is not used alone.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Population Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "012",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639474",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639474",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--F"
},
{
"entContent": {
"_uniqueProp": "012_PVS1_nuclear_RYR1",
"additionalComments": "PVS1 is not applicable. MHS is due to gain of function variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "012",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0244",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639466",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639466",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--C"
},
{
"entContent": {
"_uniqueProp": "012_PM6_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "De novo Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "012",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639457",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639457",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--A"
},
{
"entContent": {
"_uniqueProp": "012_PP5_nuclear_RYR1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"RYR1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "012",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433085",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433085",
"modified": "2022-01-19T20:31:31.799Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--O"
},
{
"entContent": {
"_uniqueProp": "012_PP3_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "012",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product\n * Use REVEL score of >0.85",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0062",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639470",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639470",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--N"
},
{
"entContent": {
"_uniqueProp": "012_PP2_nuclear_RYR1",
"additionalComments": "PP2 is not applicable. RYR1 does not appear to be constrained for missense variation with a z-score of 1.92 in gnomAD.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Functional Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "012",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639469",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639469",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--M"
},
{
"entContent": {
"_uniqueProp": "012_BP5_nuclear_RYR1",
"additionalComments": "BP5 is not applicable as individuals have been described with MHS and two pathogenic variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Other Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "012",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639467",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639467",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--L"
},
{
"entContent": {
"_uniqueProp": "012_BP4_nuclear_RYR1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "012",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639463",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639463",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--B"
},
{
"entContent": {
"_uniqueProp": "012_BS4_nuclear_RYR1",
"additionalComments": "BS4 is not applicable. Phenotype for MHS is routinely determined based on the vitro contraction test (IVCT) that has a false positive rate of approximately 6% (PP1) or the caffeine-halothane contracture test (CHCT). As the phenotype in individuals who have not experienced an MH crisis cannot be reliably determined BS4 is not utilized.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Segregation Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "012",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639456",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639456",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--D"
},
{
"entContent": {
"_uniqueProp": "012_BP1_nuclear_RYR1",
"additionalComments": "BP1 is not applicable. MH is caused primarily by missense variants in RYR1.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "012",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639455",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639455",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--E"
},
{
"entContent": {
"_uniqueProp": "012_PM4_nuclear_RYR1",
"additionalComments": "PM4 is not applicable. The majority of RYR1 variants that are causative for MHS are missense variants.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0018493"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"RYR1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "012",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135639452",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135639452",
"modified": "2022-01-19T20:33:34.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--C"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018493",
"lbl": "malignant hyperthermia of anesthesia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/malignant_hyperthermia"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0002254"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020844"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/9867"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D008305"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/405501007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0024591"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_8545"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84869"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_423"
}
],
"definition": {
"val": "A pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gasses such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, to stresses such as vigorous exercise and heat.",
"xrefs": [
"Orphanet:423",
"https://orcid.org/0000-0001-5208-3432"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "anaesthesia related hyperthermia"
},
{
"pred": "hasExactSynonym",
"val": "anesthesia related hyperthermia",
"xrefs": [
"DOID:8545"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "hyperthermia of anaesthesia"
},
{
"pred": "hasExactSynonym",
"val": "hyperthermia of anesthesia",
"xrefs": [
"Orphanet:423"
]
},
{
"pred": "hasExactSynonym",
"val": "malignant hyperpyrexia",
"xrefs": [
"NCIT:C84869"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "malignant hyperpyrexia due to anaesthesia"
},
{
"pred": "hasExactSynonym",
"val": "malignant hyperpyrexia due to anesthesia",
"xrefs": [
"DOID:8545"
]
},
{
"pred": "hasExactSynonym",
"val": "malignant hyperthermia",
"xrefs": [
"DOID:8545",
"MONDO:ambiguous",
"NCIT:C84869"
]
},
{
"pred": "hasExactSynonym",
"val": "malignant hyperthermia of anesthesia",
"xrefs": [
"Orphanet:423"
]
},
{
"pred": "hasExactSynonym",
"val": "malignant hyperthermia syndrome",
"xrefs": [
"NCIT:C84869"
]
}
],
"xrefs": [
{
"val": "DOID:8545"
},
{
"val": "GARD:6964"
},
{
"val": "HP:0002047"
},
{
"val": "ICD9:995.86"
},
{
"val": "MEDGEN:9867"
},
{
"val": "MESH:D008305"
},
{
"val": "MedDRA:10020844"
},
{
"val": "NCIT:C84869"
},
{
"val": "Orphanet:423"
},
{
"val": "SCTID:405501007"
},
{
"val": "UMLS:C0024591"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018493",
"name": "malignant hyperthermia of anesthesia"
},
"entId": "MONDO:0018493",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018493",
"entType": "Disease",
"ldhId": "135642187",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642187",
"modified": "2025-10-07T15:46:26.937Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YOUq---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962312831000,
"agr": "HGNC:10483",
"alias_name": [
"protein phosphatase 1, regulatory subunit 137"
],
"alias_symbol": [
"RYR",
"PPP1R137"
],
"ccds_id": [
"CCDS42563",
"CCDS33011"
],
"date_approved_reserved": "1989-12-01",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-25",
"ena": [
"J05200"
],
"ensembl_gene_id": "ENSG00000196218",
"entrez_id": "6261",
"gene_group": [
"Ryanodine receptors",
"Protein phosphatase 1 regulatory subunits"
],
"gene_group_id": [
287,
694
],
"hgnc_id": "HGNC:10483",
"iuphar": "objectId:747",
"location": "19q13.2",
"location_sortable": "19q13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Leiden Muscular Dystrophy pages|http://www.dmd.nl/nmdb2/home.php?select_db=RYR1",
"LRG_766|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_766.xml"
],
"mane_select": [
"ENST00000359596.8",
"NM_000540.3"
],
"mgd_id": [
"MGI:99659"
],
"name": "ryanodine receptor 1",
"omim_id": [
"180901"
],
"orphanet": 118437,
"prev_name": [
"central core disease of muscle",
"ryanodine receptor 1 (skeletal)"
],
"prev_symbol": [
"MHS",
"MHS1",
"CCO"
],
"pubmed_id": [
1862346,
16621918
],
"refseq_accession": [
"NM_000540"
],
"rgd_id": [
"RGD:1586637"
],
"status": "Approved",
"symbol": "RYR1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002oit.4",
"uniprot_ids": [
"P21817"
],
"uuid": "3bbc9355-dfa8-466c-9ee0-3e879340392a",
"vega_id": "OTTHUMG00000182403"
},
"NCBI": {
"id": "6261"
}
},
"entId": "RYR1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10483",
"entType": "Gene",
"ldhId": "135641927",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641927",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "012_nuclear_RYR1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0018493",
"preferredTitle": "malignant hyperthermia of anesthesia"
}
],
"gene": "RYR1",
"preferredTranscript": "NM_000540.3"
}
],
"ns": "012"
},
"entType": "RuleSet",
"ldhId": "135641053",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641053",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--A"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-11-28T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-07-09T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-09T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-12-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Malignant Hyperthermia Susceptibility",
"shortBaseName": "MHS",
"shortTitle": "Malignant Hyperthermia Susceptibility VCEP",
"title": "Malignant Hyperthermia Susceptibility Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50038",
"entIri": "https://www.clinicalgenome.org/affiliation/50038",
"entType": "Organization",
"ldhId": "135637651",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637651",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637584",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637584",
"modified": "2023-09-29T15:16:47.385Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK---"
},
{
"entContent": {
"approvedOn": "2021-11-09T00:00:00.000Z",
"description": "This version is specified for the following genes: LDLR",
"namespace": "GN013",
"notes": "",
"references": [],
"releaseNotes": "Updated for clarification on PM3 and BP2, and typo correction.",
"shortTitle": "ACMG variant classification Familial Hypercholesterolemia",
"specificationSource": "https://clinicalgenome.org/docs/clingen-familial-hypercholesterolemia-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1-2/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-09T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"013"
],
"title": "ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2",
"version": "1.2.0"
},
"entId": "GN013",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "013_PM2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "013",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637716",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637716",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--B"
},
{
"entContent": {
"_uniqueProp": "013_BP7_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "013",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant is synonymous.\nCaveat: variant must also meet BP4 (i.e. no predicted impact on splicing).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637713",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637713",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--C"
},
{
"entContent": {
"_uniqueProp": "013_BA1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "013",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637710",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637710",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--B"
},
{
"entContent": {
"_uniqueProp": "013_PVS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "013",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flow diagram (Figure 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637708",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637708",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoO--_"
},
{
"entContent": {
"_uniqueProp": "013_BS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "013",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637691",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637691",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoK---"
},
{
"entContent": {
"_uniqueProp": "013_PP3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "013",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637712",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637712",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--A"
},
{
"entContent": {
"_uniqueProp": "013_PP2_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "013",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637711",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637711",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--P"
},
{
"entContent": {
"_uniqueProp": "013_BP5_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Other Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "013",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637709",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637709",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--G"
},
{
"entContent": {
"_uniqueProp": "013_PP1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Segregation Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "013",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637706",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637706",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoO---"
},
{
"entContent": {
"_uniqueProp": "013_BP4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "013",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637705",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637705",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--_"
},
{
"entContent": {
"_uniqueProp": "013_BP3_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "013",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637703",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637703",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--O"
},
{
"entContent": {
"_uniqueProp": "013_PS1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "013",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.\nCaveat: there is no in silico predicted splicing impact for either variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637700",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637700",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--A"
},
{
"entContent": {
"_uniqueProp": "013_BP1_nuclear_LDLR",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "013",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Missense variant in gene where only LOF causes disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637697",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637697",
"modified": "2022-01-19T20:33:34.697Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--H"
},
{
"entContent": {
"_uniqueProp": "013_BS3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "013",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant meets Level 1 benign functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.\nNote: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant meets Level 3 benign functional study criteria. See Table 3.\n(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.\n(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).\n(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.\n(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.\n(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637695",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637695",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe---"
},
{
"entContent": {
"_uniqueProp": "013_BS2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "013",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637693",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637693",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxom---"
},
{
"entContent": {
"_uniqueProp": "013_BP6_nuclear_LDLR",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"LDLR"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "013",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433114",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433114",
"modified": "2022-01-19T20:31:32.045Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--P"
},
{
"entContent": {
"_uniqueProp": "013_PS4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Population Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "013",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).\nCaveat: variant must also meet PM2",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637707",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637707",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--B"
},
{
"entContent": {
"_uniqueProp": "013_PS3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "013",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant meets Level 1 pathogenic functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant meets Level 2 pathogenic functional study criteria. See Table 3.\n(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.\n(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant meets Level 3 pathogenic functional study criteria. See Table 3.\n (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).\n (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.\n (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.\n (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637704",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637704",
"modified": "2021-11-05T21:11:03.168Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--T"
},
{
"entContent": {
"_uniqueProp": "013_PM6_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "De novo Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "013",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637699",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637699",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--A"
},
{
"entContent": {
"_uniqueProp": "013_PM5_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "013",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationtype": [
"Clarification"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637696",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637696",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW---"
},
{
"entContent": {
"_uniqueProp": "013_PM3_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Allelic Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "013",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637692",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637692",
"modified": "2021-11-12T23:33:06.714Z",
"modifier": "neethus",
"rev": "_h6SHxoq--J"
},
{
"entContent": {
"_uniqueProp": "013_PP5_nuclear_LDLR",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"LDLR"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "013",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433115",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433115",
"modified": "2022-01-19T20:31:32.045Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--Q"
},
{
"entContent": {
"_uniqueProp": "013_PM1_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Functional Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "013",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637715",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637715",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--C"
},
{
"entContent": {
"_uniqueProp": "013_PP4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Other Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "013",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.\nCaveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637714",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637714",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--B"
},
{
"entContent": {
"_uniqueProp": "013_PS2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "De novo Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "013",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637702",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637702",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--_"
},
{
"entContent": {
"_uniqueProp": "013_BP2_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Allelic Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "013",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637701",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637701",
"modified": "2021-11-12T23:33:06.714Z",
"modifier": "neethus",
"rev": "_h6SHxoi--H"
},
{
"entContent": {
"_uniqueProp": "013_BS4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Segregation Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "013",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.\nCaveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637698",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637698",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--_"
},
{
"entContent": {
"_uniqueProp": "013_PM4_nuclear_LDLR",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007750"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"LDLR"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "013",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.\nCaveat: variant must also meet PM2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637694",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637694",
"modified": "2021-11-05T21:07:11.693Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007750",
"lbl": "hypercholesterolemia, familial, 1",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4882"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007750"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypercholesterolemia_familial_1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/152875"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/398036000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0745103"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/143890"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "FHCL1",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasExactSynonym",
"val": "LDL cholesterol level QTL2"
},
{
"pred": "hasExactSynonym",
"val": "LDL receptor disorder",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasExactSynonym",
"val": "hypercholesterolemia, familial"
},
{
"pred": "hasExactSynonym",
"val": "hypercholesterolemia, familial, 1",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasExactSynonym",
"val": "hypercholesterolemia, familial, due to ldlr defect, modifier of"
},
{
"pred": "hasExactSynonym",
"val": "hypercholesterolemia, familial, modifier of"
},
{
"pred": "hasExactSynonym",
"val": "hypercholesterolemic xanthomatosis, familial",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasExactSynonym",
"val": "hyperlipoproteinemia, type 2",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasExactSynonym",
"val": "hyperlipoproteinemia, type 2A",
"xrefs": [
"OMIM:143890"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "FHC"
},
{
"pred": "hasRelatedSynonym",
"val": "hyper-low-density-lipoproteinemia"
},
{
"pred": "hasRelatedSynonym",
"val": "hypercholesterolemia, susceptibility to"
},
{
"pred": "hasRelatedSynonym",
"val": "low density lipoprotein cholesterol level quantitative trait locus 2"
}
],
"xrefs": [
{
"val": "MEDGEN:152875"
},
{
"val": "NANDO:2200602"
},
{
"val": "OMIM:143890"
},
{
"val": "SCTID:398036000"
},
{
"val": "UMLS:C0745103"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007750",
"name": "hypercholesterolemia, familial, 1"
},
"entId": "MONDO:0007750",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007750",
"entType": "Disease",
"ldhId": "135641990",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641990",
"modified": "2025-10-07T15:43:31.749Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7VjFC---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056951218897000,
"agr": "HGNC:6547",
"alias_name": [
"familial hypercholesterolemia"
],
"alias_symbol": [
"LDLCQ2"
],
"ccds_id": [
"CCDS58651",
"CCDS56083",
"CCDS56085",
"CCDS12254",
"CCDS56084"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2008-08-01",
"ena": [
"AY114155"
],
"ensembl_gene_id": "ENSG00000130164",
"entrez_id": "3949",
"gene_group": [
"Low density lipoprotein receptors",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
634,
1691
],
"hgnc_id": "HGNC:6547",
"location": "19p13.2",
"location_sortable": "19p13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"UCL LDLR-LOVD, British Heart Foundation variant database|http://databases.lovd.nl/shared/genes/LDLR",
"UMD Locus Specific Databases|http://www.umd.be/",
"LRG_274|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_274.xml"
],
"mane_select": [
"ENST00000558518.6",
"NM_000527.5"
],
"mgd_id": [
"MGI:96765"
],
"name": "low density lipoprotein receptor",
"omim_id": [
"606945"
],
"orphanet": 123021,
"refseq_accession": [
"NM_000527"
],
"rgd_id": [
"RGD:2998"
],
"status": "Approved",
"symbol": "LDLR",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002mqk.5",
"uniprot_ids": [
"P01130"
],
"uuid": "e2285147-2183-41ee-ab27-666ba06a50bb",
"vega_id": "OTTHUMG00000171935"
},
"NCBI": {
"id": "3949"
}
},
"entId": "LDLR",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6547",
"entType": "Gene",
"ldhId": "135641793",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641793",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "013_nuclear_LDLR",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0007750",
"preferredTitle": "hypercholesterolemia, familial"
}
],
"gene": "LDLR",
"preferredTranscript": "NM_000527.5"
}
],
"ns": "013"
},
"entType": "RuleSet",
"ldhId": "135640393",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135640393",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--_"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approvalDate": "2017-08-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-09-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-12-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Familial Hypercholesterolemia",
"shortBaseName": "FH",
"shortTitle": "Familial Hypercholesterolemia VCEP",
"title": "Familial Hypercholesterolemia Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50004",
"entIri": "https://www.clinicalgenome.org/affiliation/50004",
"entType": "Organization",
"ldhId": "135637628",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637628",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--B"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637573",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637573",
"modified": "2023-09-29T15:16:47.524Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---B"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "014_PP5_nuclear_ETHE1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ETHE1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433226",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433226",
"modified": "2022-01-19T20:31:32.900Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--A"
},
{
"entContent": {
"_uniqueProp": "014_BP6_nuclear_PDHA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PDHA1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433171",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433171",
"modified": "2022-01-19T20:31:32.588Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--E"
},
{
"entContent": {
"_uniqueProp": "014_BP5_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Other Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "014",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637949",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637949",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--e"
},
{
"entContent": {
"_uniqueProp": "014_BP3_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "014",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637943",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637943",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--d"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637922",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637922",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--X"
},
{
"entContent": {
"_uniqueProp": "014_PS2_nuclear_POLG",
"additionalComments": "Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "De novo Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "014",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637916",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637916",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--K"
},
{
"entContent": {
"_uniqueProp": "014_BP2_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Allelic Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "014",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637915",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637915",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--A"
},
{
"entContent": {
"_uniqueProp": "014_PS1_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "014",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637914",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637914",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxou---"
},
{
"entContent": {
"_uniqueProp": "014_BS2_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "014",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual in the homozygous state AND/OR Normal mtDNA content (1. Must be performed in muscle and/or liver; blood, fibroblast, and buccal not acceptable; 2. Must be performed in children only - defined as <18 years old; 3. A normal level is defined as >50%.)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of COX negative fibers in muscle (children and adults)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637907",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637907",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--X"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_PDHA1",
"additionalComments": "MAF - 0.0000092 (<0.00092%). Note: Per SVI: Use a threshold an order of magnitude",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Population Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "014",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "0.0000092 (<0.00092%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637904",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--W"
},
{
"entContent": {
"_uniqueProp": "014_PP2_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Functional Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637899",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637899",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--L"
},
{
"entContent": {
"_uniqueProp": "014_BA1_nuclear_PDHA1",
"additionalComments": "MAF - >0.00092 (>0.092%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 100%, Penetrance - 100%. Notes Utilized biallelic inheritance in WARE calculator (monoallelic cut-off calculated out to even 1 occurrence in gnomAD meeting BA1 so utilized biallelic); for genetic heterogeneity, 84% was used (Patel et al., 2012; page 388)",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Population Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "014",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": ">0.00092 (>0.092%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637898",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637898",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--T"
},
{
"entContent": {
"_uniqueProp": "014_PS4_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Population Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637895",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--K"
},
{
"entContent": {
"_uniqueProp": "014_BP4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637893",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637893",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--B"
},
{
"entContent": {
"_uniqueProp": "014_BP1_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637885",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637885",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--K"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_PDHA1",
"additionalComments": "MAF - >>0.00092 (>0.092%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 10% (Estimated; Patel et al., 2012 - Supp table, Penetrance - 100%.",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Population Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "014",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.000092 (>0.0092%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637879",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637879",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Q"
},
{
"entContent": {
"_uniqueProp": "014_BA1_nuclear_SLC19A3",
"additionalComments": "MAF - >0.001 (0.1%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 100%, Penetrance - 100%",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "014",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": ">0.001 (>0.1%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637872",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637872",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--F"
},
{
"entContent": {
"_uniqueProp": "014_PS4_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637869",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637869",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--L"
},
{
"entContent": {
"_uniqueProp": "014_BS4_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637860",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637860",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--E"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637858",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637858",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--L"
},
{
"entContent": {
"_uniqueProp": "014_BP6_nuclear_POLG",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"POLG"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433198",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433198",
"modified": "2022-01-19T20:31:32.743Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--_"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Functional Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "014",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637955",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637955",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxom---"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "De novo Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "014",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637939",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637939",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--a"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use per SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637932",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637932",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--S"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_ETHE1",
"additionalComments": "MAF - >0.01(>1.0%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 20% (estimated), Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "014",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.0002 (>0.020%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637931",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637931",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--C"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_POLG",
"additionalComments": "Per SVI: Use a threshold an order of magnitude below BS1 threshold",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "014",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "<0.0005 (<0.05% )",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637930",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637930",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--E"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "014",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637929",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637929",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--Q"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Other Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1. Mitochondrial DNA depletion showing ≤ 20% of controls, OR \n2. Multiple mitochondrial DNA deletions (NOTE:depletion and/or deletion analysis must be performed in muscle and/or liver; other tissues such as blood, fibroblast, and buccal are not acceptable; Must be performed in child, as defined as <18 years old) \nNote: For both scenarios 1 and 2, will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1. Mitochondrial DNA depletion showing 20-50% of controls in children (< 18 years of age), AND/OR \n2. COX negative fibers in muscle in children and/or adults\nNote: Will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637928",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637928",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Y"
},
{
"entContent": {
"_uniqueProp": "014_PP1_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Segregation Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Further define “affected” as an individual in whom there is objective evidence of manifestations consistent with POLG-related disorders spectrum: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and/or progressive external ophthalmoplegia (PEO)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637920",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637920",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--W"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_POLG",
"additionalComments": "MAF - >0.005 (>0.5%), Prevalence - 1/10,000 , Allelic Heterogeneity - 50% (estimated), Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "014",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.005 (>0.5% - AR)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637905",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--I"
},
{
"entContent": {
"_uniqueProp": "014_BP7_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "014",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637901",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637901",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--V"
},
{
"entContent": {
"_uniqueProp": "014_PP1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637894",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637894",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--L"
},
{
"entContent": {
"_uniqueProp": "014_BS3_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Functional Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637883",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637883",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--J"
},
{
"entContent": {
"_uniqueProp": "014_PM4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "014",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637882",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637882",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--N"
},
{
"entContent": {
"_uniqueProp": "014_BS2_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Population Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "014",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in at least two healthy male adults. Note: Individual’s phenotype is well-characterized (not just seen in database of presumed healthy individuals) AND/OR ≥16 hemizygotes in gnomAD",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in 4-15 hemizygotes in gnomAD AND/OR Pyruvate radioactive enzyme assay showing normal (defined as >3rd percentile of controls) for PDC, activated and normal ratios (PDC/E3 and/or PDC/CS) in fibroblasts with no evidence of skewed X-inactivation in fibroblasts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637881",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637881",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--I"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient has/had MRI features of Leigh syndrome with clinical response to biotin/thiamine",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637876",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637876",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Q"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637874",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637874",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--L"
},
{
"entContent": {
"_uniqueProp": "014_PP2_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637873",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637873",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--I"
},
{
"entContent": {
"_uniqueProp": "014_BP4_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637867",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637867",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--E"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "014",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637861",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637861",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--D"
},
{
"entContent": {
"_uniqueProp": "014_PP5_nuclear_PDHA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PDHA1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433172",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433172",
"modified": "2022-01-19T20:31:32.588Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--R"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Other Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Individual has abnormally high urinary ethylmalonic acid AND one of the following: \n(1) All of the following symptoms present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay \n(2) ≥3 or more of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle (without evidence of other complexes decreased)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Individual has abnoramlly high urinary ethylmalonic acid AND one of the following: \n(1) 3 of the following features present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay \n(2) abnormal laboratory studies in 2 of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle, without evidence of other complexes decreased",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637954",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637954",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe---"
},
{
"entContent": {
"_uniqueProp": "014_BP7_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "014",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637953",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637953",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--C"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637952",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637952",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--A"
},
{
"entContent": {
"_uniqueProp": "014_BP4_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637945",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637945",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--A"
},
{
"entContent": {
"_uniqueProp": "014_PS1_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "014",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637940",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637940",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--b"
},
{
"entContent": {
"_uniqueProp": "014_BP1_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637937",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637937",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--J"
},
{
"entContent": {
"_uniqueProp": "014_BS2_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "014",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual in the homozygous state",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Normal laboratory values (specific labs outlined in PP4)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637933",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637933",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--D"
},
{
"entContent": {
"_uniqueProp": "014_BP7_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "014",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637927",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637927",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--D"
},
{
"entContent": {
"_uniqueProp": "014_PP2_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637925",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637925",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--O"
},
{
"entContent": {
"_uniqueProp": "014_BA1_nuclear_POLG",
"additionalComments": "MAF - >0.01(>1.0%), Prevalence - 1/10,000 (POLG Genereviews), Allelic Heterogeneity - 100%, Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "014",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": ">0.01 (>1%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637924",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637924",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--B"
},
{
"entContent": {
"_uniqueProp": "014_PS3_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637918",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637918",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--N"
},
{
"entContent": {
"_uniqueProp": "014_BP3_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "014",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637917",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637917",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--Q"
},
{
"entContent": {
"_uniqueProp": "014_BP1_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637911",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637911",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---_"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637910",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637910",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--K"
},
{
"entContent": {
"_uniqueProp": "014_PM4_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "014",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637908",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637908",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--J"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Functional Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "014",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in one of the following functional domains:\n * thiamine pyrophosphate (TPP) binding site (aa positions 118Y, 119R, 165G, 167V, 195G, 196D, 197G, 198A, 225N, 227Y, 292H).\n * α β heterodimer interface (aa positions 160F, 162G, 164N, 169A, 172P, 173L, 176G, 177I, 179L, 180A,183Y, 202G,203Q, 209N, 210M, 213L).\n * α2 β2 heterotetramer interface (aa positions 88R, 140G, 165G, 166I, 197G, 199A, 200N, 201Q, 202G, 205F, 209N, 213L, 228G, 229M, 230G, 231T, 245R, 296D, 300S).\n * Phosphorylation loop region (aa positions 287Y, 288R, 289Y, 290H, 291G, 292H, 293S, 295S, 296D, 297P, 298G, 299V, 300S, 301Y, 302R, 303T, 304R, 305E, 314S, 315D, 316P).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637903",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637903",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--R"
},
{
"entContent": {
"_uniqueProp": "014_PS3_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Transporter assay showing loss of function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637866",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637866",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--M"
},
{
"entContent": {
"_uniqueProp": "014_BP2_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "014",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637863",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637863",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--P"
},
{
"entContent": {
"_uniqueProp": "014_PM4_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "014",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637856",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637856",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--D"
},
{
"entContent": {
"_uniqueProp": "014_BS2_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "014",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy, untreated, adult individual in the homozygous state",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637855",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637855",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--O"
},
{
"entContent": {
"_uniqueProp": "014_BP6_nuclear_ETHE1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ETHE1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433225",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433225",
"modified": "2022-01-19T20:31:32.900Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--F"
},
{
"entContent": {
"_uniqueProp": "014_PP5_nuclear_SLC19A3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC19A3"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433145",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433145",
"modified": "2022-01-19T20:31:32.423Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--A"
},
{
"entContent": {
"_uniqueProp": "014_BP6_nuclear_SLC19A3",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC19A3"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433144",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433144",
"modified": "2022-01-19T20:31:32.423Z",
"modifier": "genbadmin",
"rev": "_h6SHxom---"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "014",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "<0.00002 (<0.0020%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637956",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637956",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--F"
},
{
"entContent": {
"_uniqueProp": "014_PP2_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Functional Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637951",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637951",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---A"
},
{
"entContent": {
"_uniqueProp": "014_PS3_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Functional Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Reduced ETHE1 persulfide dioxygenase",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637944",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637944",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--G"
},
{
"entContent": {
"_uniqueProp": "014_PS2_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "De novo Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "014",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637942",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637942",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--_"
},
{
"entContent": {
"_uniqueProp": "014_BS4_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Segregation Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637938",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637938",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--F"
},
{
"entContent": {
"_uniqueProp": "014_BS3_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Functional Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637935",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637935",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--H"
},
{
"entContent": {
"_uniqueProp": "014_BP4_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively. Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637919",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637919",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Y"
},
{
"entContent": {
"_uniqueProp": "014_BS4_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Segregation Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637912",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637912",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--L"
},
{
"entContent": {
"_uniqueProp": "014_BS3_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Functional Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637909",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637909",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--M"
},
{
"entContent": {
"_uniqueProp": "014_PS3_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Functional Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637892",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637892",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxp----"
},
{
"entContent": {
"_uniqueProp": "014_PS1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "014",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637888",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637888",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--A"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "De novo Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "014",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637887",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637887",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--_"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637884",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637884",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--R"
},
{
"entContent": {
"_uniqueProp": "014_PM2_nuclear_SLC19A3",
"additionalComments": "MAF - ><0.00005 (0.0050%). Notes: Per SVI: Use a threshold an order of magnitude below BS1 threshold",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "014",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "<0.00005 (<0.0050%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0030",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637878",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637878",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--H"
},
{
"entContent": {
"_uniqueProp": "014_PM1_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "014",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637877",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637877",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--I"
},
{
"entContent": {
"_uniqueProp": "014_PP5_nuclear_POLG",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"POLG"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "014",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433199",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433199",
"modified": "2022-01-19T20:31:32.743Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--B"
},
{
"entContent": {
"_uniqueProp": "014_BA1_nuclear_ETHE1",
"additionalComments": "MAF - >0.01(>1.0%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 100%, Penetrance - 100%. ",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "014",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": ">0.001 (>0.1%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637950",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637950",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--B"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637948",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637948",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--M"
},
{
"entContent": {
"_uniqueProp": "014_PS4_nuclear_ETHE1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Population Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637947",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637947",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--R"
},
{
"entContent": {
"_uniqueProp": "014_PP1_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Segregation Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637946",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637946",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Z"
},
{
"entContent": {
"_uniqueProp": "014_BP2_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Allelic Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "014",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637941",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637941",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--c"
},
{
"entContent": {
"_uniqueProp": "014_PM5_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "014",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637936",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637936",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--Z"
},
{
"entContent": {
"_uniqueProp": "014_PM4_nuclear_ETHE1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011229"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ETHE1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "014",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637934",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637934",
"modified": "2021-11-05T21:07:13.391Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--E"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively\n * Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637926",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637926",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa---"
},
{
"entContent": {
"_uniqueProp": "014_BP5_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Other Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "014",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637923",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637923",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxom---"
},
{
"entContent": {
"_uniqueProp": "014_PS4_nuclear_POLG",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Population Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "014",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Rarely, pathogenic variants cause disease in an AD manner. For these variants only, presence in: 2 unrelated probands will be considered supporting evidence, 4 unrelated probands will be considered moderate evidence, 16 unrelated probands will be strong evidence.\n * Note: This will only be utilized when there is segregation evidence supporting autosomal dominant inheritance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637921",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637921",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--L"
},
{
"entContent": {
"_uniqueProp": "014_PM6_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "De novo Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "014",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637913",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637913",
"modified": "2021-11-05T21:07:13.334Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--M"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_POLG",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0044970"
],
"evidenceCategory": "Allelic Data",
"gene": [
"POLG"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use per SVI guidance.\nNote: T251I and P587L are almost always in cis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637906",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637906",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--D"
},
{
"entContent": {
"_uniqueProp": "014_PP4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Other Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "014",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One of the following criteria are met: \n(1) Pyruvate radioactive enzyme assay showing decreased (as defined as <3rd percentile of controls) for PDC, activated and decreased ratios (PDC/E3 and/or PDC/CS) in fibroblasts, muscle, and/or lymphocytes; \n(2) other assays showing decrease in PDC activity (ie: western blot, immunocapture, and activity; commercial kits for research); \n(3) abnormally high pyruvate and/or pyruvate/lactate ratio",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637902",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637902",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--V"
},
{
"entContent": {
"_uniqueProp": "014_PP3_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "014",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637900",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637900",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--U"
},
{
"entContent": {
"_uniqueProp": "014_BP5_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Other Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "014",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637897",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--J"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637896",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--C"
},
{
"entContent": {
"_uniqueProp": "014_BP3_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "014",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637891",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637891",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--S"
},
{
"entContent": {
"_uniqueProp": "014_PS2_nuclear_PDHA1",
"additionalComments": "Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "De novo Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "014",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637890",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637890",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--H"
},
{
"entContent": {
"_uniqueProp": "014_BP2_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "014",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637889",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637889",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--G"
},
{
"entContent": {
"_uniqueProp": "014_BS4_nuclear_PDHA1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Segregation Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "014",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected and/or treated members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637886",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637886",
"modified": "2021-11-05T21:07:13.238Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa---"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_PDHA1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0019169"
],
"evidenceCategory": "Allelic Data",
"gene": [
"PDHA1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637880",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637880",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--J"
},
{
"entContent": {
"_uniqueProp": "014_BP7_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "014",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637875",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637875",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--G"
},
{
"entContent": {
"_uniqueProp": "014_BP5_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "014",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637871",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637871",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--G"
},
{
"entContent": {
"_uniqueProp": "014_PVS1_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "014",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Applied per PVS1 flowsheet of Abou Toyoun et al.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0026",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637870",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637870",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--U"
},
{
"entContent": {
"_uniqueProp": "014_PP1_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "014",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For segregation, an affected is defined as an individual who \n1) has brainstem or basal ganglia lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease OR \n2) a person with neurodevelopmental regression or MRI lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease who had significant clinical improvement in either symptoms or MRI lesions from treatment with biotin and thiamine.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637868",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637868",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--J"
},
{
"entContent": {
"_uniqueProp": "014_BP3_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "014",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637865",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637865",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--K"
},
{
"entContent": {
"_uniqueProp": "014_PS2_nuclear_SLC19A3",
"additionalComments": "Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "014",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo in a patient with the disease and no family history",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637864",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637864",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--F"
},
{
"entContent": {
"_uniqueProp": "014_PS1_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "014",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637862",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637862",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--J"
},
{
"entContent": {
"_uniqueProp": "014_BP1_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "014",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637859",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637859",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--H"
},
{
"entContent": {
"_uniqueProp": "014_BS3_nuclear_SLC19A3",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "014",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Transporter assay showing no effect on the gene or gene product",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637857",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637857",
"modified": "2022-01-19T20:33:34.959Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--K"
},
{
"entContent": {
"_uniqueProp": "014_PM3_nuclear_SLC19A3",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "014",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use per SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637854",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637854",
"modified": "2021-11-05T21:11:03.348Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--P"
},
{
"entContent": {
"_uniqueProp": "014_BS1_nuclear_SLC19A3",
"additionalComments": "MAF - >0.0005 (0.050%), Prevalence - <1/1,000,000, Allelic Heterogeneity - 50.4% [63/125 (c.1264A>G); PMID: 28696212], Penetrance - 100%",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0011841"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC19A3"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "014",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": ">0.0005 (>0.050%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135637853",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135637853",
"modified": "2021-11-05T21:07:13.150Z",
"modifier": "genbadmin",
"rev": "_h6SHxoW--K"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0044970",
"lbl": "mitochondrial disease",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0044970"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/specific_disease_by_dysfunctional_structure.yaml"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://www.epilepsydiagnosis.org/aetiology/metabolic-groupoverview.html#mitochondrial"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/155901"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0751651"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#harrisons_view",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare_grouping"
],
"xrefs": [
{
"val": "MEDGEN:155901"
},
{
"val": "NANDO:1200173"
},
{
"val": "NANDO:2100163"
},
{
"val": "UMLS:C0751651"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0044970",
"name": "mitochondrial disease"
},
"entId": "MONDO:0044970",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0044970",
"entType": "Disease",
"ldhId": "135642194",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642194",
"modified": "2025-10-07T15:48:22.065Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7a-qO---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011841",
"lbl": "biotin-responsive basal ganglia disease",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4205"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/basal_ganglia_disease_biotin_thiamine_responsive"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005527"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1776831202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/375289"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C537658"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/703522009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/723557004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1843807"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050659"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199348"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_65284"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/607483"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BBGD",
"xrefs": [
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BTBGD",
"xrefs": [
"OMIM:607483",
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"val": "biotin-thiamine-responsive basal ganglia disease",
"xrefs": [
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"val": "thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2)"
},
{
"pred": "hasExactSynonym",
"val": "thiamine-responsive encephalopathy",
"xrefs": [
"MONDO:0016050",
"Orphanet:199348"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "THMD2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "basal ganglia disease, biotin-responsive"
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, thiamine-responsive"
},
{
"pred": "hasRelatedSynonym",
"val": "thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive type)",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0050659"
},
{
"val": "GARD:10237"
},
{
"val": "ICD9:333.99"
},
{
"val": "MEDGEN:375289"
},
{
"val": "MESH:C537658"
},
{
"val": "OMIM:607483"
},
{
"val": "Orphanet:199348"
},
{
"val": "Orphanet:65284"
},
{
"val": "SCTID:703522009"
},
{
"val": "SCTID:723557004"
},
{
"val": "UMLS:C1843807"
},
{
"val": "icd11.foundation:1776831202"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011841",
"name": "biotin-responsive basal ganglia disease"
},
"entId": "MONDO:0011841",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011841",
"entType": "Disease",
"ldhId": "135642197",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642197",
"modified": "2025-10-07T15:44:35.158Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wh-W---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019169",
"lbl": "pyruvate dehydrogenase deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100033"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/specific_disease_by_dysfunctional_structure.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1124597954"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/19610"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/46683007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0034345"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3649"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C103968"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_765"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS312170"
}
],
"definition": {
"val": "A rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency.",
"xrefs": [
"Orphanet:765"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDH",
"xrefs": [
"NCIT:C103968",
"Orphanet:765"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDHC",
"xrefs": [
"Orphanet:765"
]
},
{
"pred": "hasExactSynonym",
"val": "Pyruvate Dehydrogenase Complex Deficiency",
"xrefs": [
"NORD:1641",
"OMIMPS:312170",
"Orphanet:765",
"icd11.foundation:1124597954"
]
},
{
"pred": "hasExactSynonym",
"val": "deficiency of pyruvic dehydrogenase",
"xrefs": [
"DOID:3649"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate decarboxylase deficiency",
"xrefs": [
"DOID:3649",
"MONDO:0005934"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase complex deficiency",
"xrefs": [
"OMIMPS:312170",
"Orphanet:765",
"icd11.foundation:1124597954"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase complex deficiency disease",
"xrefs": [
"DOID:3649"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase deficiency",
"xrefs": [
"DOID:3649",
"NCIT:C103968",
"Orphanet:765",
"icd11.foundation:1124597954"
]
}
],
"xrefs": [
{
"val": "DOID:3649"
},
{
"val": "GARD:7513"
},
{
"val": "ICD9:277.89"
},
{
"val": "MEDGEN:19610"
},
{
"val": "NANDO:2200518"
},
{
"val": "NCIT:C103968"
},
{
"val": "NORD:1641"
},
{
"val": "OMIMPS:312170"
},
{
"val": "Orphanet:765"
},
{
"val": "SCTID:46683007"
},
{
"val": "UMLS:C0034345"
},
{
"val": "icd11.foundation:1124597954"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019169",
"name": "pyruvate dehydrogenase deficiency"
},
"entId": "MONDO:0019169",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019169",
"entType": "Disease",
"ldhId": "135642195",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642195",
"modified": "2025-10-07T15:46:39.824Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Ya3e---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011229",
"lbl": "ethylmalonic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5671"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/encephalopathy_ethylmalonic"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/2198/ethylmalonic-encephalopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1966714550"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/355966"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535737"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/723307008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1865349"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060640"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_51188"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/602473"
}
],
"definition": {
"val": "Ethylmalonic acid encephalopathy (EE) is defined by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.",
"xrefs": [
"Orphanet:51188"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "EE",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "EPEMA syndrome",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "eme",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, ethylmalonic",
"xrefs": [
"GARD:0002198",
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, petechiae, and ethylmalonic aciduria",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "syndrome of encephalopathy, petechiae, and ethylmalonic aciduria",
"xrefs": [
"GARD:0002198"
]
}
],
"xrefs": [
{
"val": "DOID:0060640"
},
{
"val": "GARD:2198"
},
{
"val": "MEDGEN:355966"
},
{
"val": "MESH:C535737"
},
{
"val": "OMIM:602473"
},
{
"val": "Orphanet:51188"
},
{
"val": "SCTID:723307008"
},
{
"val": "UMLS:C1865349"
},
{
"val": "icd11.foundation:1966714550"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011229",
"name": "ethylmalonic encephalopathy"
},
"entId": "MONDO:0011229",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011229",
"entType": "Disease",
"ldhId": "135642196",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642196",
"modified": "2025-10-07T15:44:25.227Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WXOy---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056966728384500,
"agr": "HGNC:12496",
"alias_name": [
"Angelman syndrome"
],
"alias_symbol": [
"AS",
"ANCR",
"E6-AP",
"FLJ26981"
],
"ccds_id": [
"CCDS45192",
"CCDS86436",
"CCDS32177",
"CCDS45191"
],
"date_approved_reserved": "1993-10-21",
"date_modified": "2021-05-26",
"date_name_changed": "2008-07-31",
"ena": [
"AF002224"
],
"ensembl_gene_id": "ENSG00000114062",
"entrez_id": "7337",
"enzyme_id": [
"2.3.2.26"
],
"gene_group": [
"HECT domain containing"
],
"gene_group_id": [
1959
],
"hgnc_id": "HGNC:12496",
"location": "15q11.2",
"location_sortable": "15q11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"NGRL, Manchester LOVD|http://ngrl.manchester.ac.uk/LOVDv.2.0/home.php?select_db=UBE3A",
"LRG_15|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_15.xml"
],
"mane_select": [
"ENST00000648336.2",
"NM_130839.5"
],
"mgd_id": [
"MGI:105098"
],
"name": "ubiquitin protein ligase E3A",
"omim_id": [
"601623"
],
"orphanet": 120365,
"prev_name": [
"human papilloma virus E6-associated protein"
],
"prev_symbol": [
"EPVE6AP",
"HPVE6A"
],
"pubmed_id": [
8221889
],
"refseq_accession": [
"NM_000462"
],
"rgd_id": [
"RGD:1306361"
],
"status": "Approved",
"symbol": "UBE3A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc059gvn.1",
"uniprot_ids": [
"Q05086"
],
"uuid": "dce8245d-bf9e-41fa-b4f2-e2a570703193",
"vega_id": "OTTHUMG00000171548"
},
"NCBI": {
"id": "7337"
}
},
"entId": "UBE3A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12496",
"entType": "Gene",
"ldhId": "135641941",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641941",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---H"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056953001476000,
"agr": "HGNC:6990",
"ccds_id": [
"CCDS14741",
"CCDS48193"
],
"date_approved_reserved": "1996-09-03",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-13",
"ena": [
"AF158180"
],
"ensembl_gene_id": "ENSG00000169057",
"entrez_id": "4204",
"gene_group": [
"Methyl-CpG binding domain containing"
],
"gene_group_id": [
1025
],
"hgnc_id": "HGNC:6990",
"location": "Xq28",
"location_sortable": "Xq28",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"RettBASE|http://mecp2.chw.edu.au/",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/MECP2",
"LRG_764|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_764.xml"
],
"mane_select": [
"ENST00000453960.7",
"NM_001110792.2"
],
"mgd_id": [
"MGI:99918"
],
"name": "methyl-CpG binding protein 2",
"omim_id": [
"300005"
],
"orphanet": 123186,
"prev_name": [
"mental retardation, X-linked 16",
"mental retardation, X-linked 79",
"Rett syndrome",
"methyl CpG binding protein 2 (Rett syndrome)",
"methyl CpG binding protein 2"
],
"prev_symbol": [
"RTT",
"MRX16",
"MRX79"
],
"pubmed_id": [
1606614,
10508514
],
"refseq_accession": [
"NM_004992"
],
"rgd_id": [
"RGD:3075"
],
"status": "Approved",
"symbol": "MECP2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004fjv.3",
"uniprot_ids": [
"P51608"
],
"uuid": "c911c5cc-315e-4631-bcdd-8627c7cc337c",
"vega_id": "OTTHUMG00000024229"
},
"NCBI": {
"id": "4202"
}
},
"entId": "MECP2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6990",
"entType": "Gene",
"ldhId": "135641938",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641938",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957870014500,
"agr": "HGNC:9179",
"alias_symbol": [
"POLG1",
"POLGA"
],
"ccds_id": [
"CCDS10350"
],
"curator_notes": [
"[Khan et al](https://www.ncbi.nlm.nih.gov/pubmed/32138667) reports that this complex locus also contains a second alternate reading frame"
],
"date_approved_reserved": "1992-02-06",
"date_modified": "2021-04-13",
"date_name_changed": "2016-07-11",
"ena": [
"X98093"
],
"ensembl_gene_id": "ENSG00000140521",
"entrez_id": "5428",
"gene_group": [
"DNA polymerases",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
535,
1691
],
"hgnc_id": "HGNC:9179",
"location": "15q26.1",
"location_sortable": "15q26.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_765|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_765.xml"
],
"mane_select": [
"ENST00000268124.11",
"NM_002693.3"
],
"mgd_id": [
"MGI:1196389"
],
"name": "DNA polymerase gamma, catalytic subunit",
"omim_id": [
"174763"
],
"orphanet": 117925,
"prev_name": [
"polymerase (DNA directed), gamma",
"polymerase (DNA) gamma, catalytic subunit"
],
"pubmed_id": [
9465903,
32138667
],
"refseq_accession": [
"NM_002693"
],
"rgd_id": [
"RGD:620057"
],
"status": "Approved",
"symbol": "POLG",
"ucsc_id": "uc002bns.5",
"uniprot_ids": [
"P54098"
],
"uuid": "3d221088-ac02-4bc9-98bf-3f9d97e8d9c9",
"vega_id": "OTTHUMG00000149646"
},
"NCBI": {
"id": "5428"
}
},
"entId": "POLG",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9179",
"entType": "Gene",
"ldhId": "135641934",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641934",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056944354918400,
"agr": "HGNC:11411",
"alias_symbol": [
"EIEE2",
"CFAP247"
],
"ccds_id": [
"CCDS14186",
"CCDS83458"
],
"date_approved_reserved": "1997-10-27",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-07",
"date_symbol_changed": "2002-11-29",
"ena": [
"Y15057"
],
"ensembl_gene_id": "ENSG00000008086",
"entrez_id": "6792",
"gene_group": [
"Cyclin dependent kinases",
"Cilia and flagella associated"
],
"gene_group_id": [
496,
1491
],
"hgnc_id": "HGNC:11411",
"iuphar": "objectId:1986",
"location": "Xp22.13",
"location_sortable": "Xp22.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/CDKL5"
],
"mane_select": [
"ENST00000623535.2",
"NM_001323289.2"
],
"mgd_id": [
"MGI:1278336"
],
"name": "cyclin dependent kinase like 5",
"omim_id": [
"300203"
],
"orphanet": 119297,
"prev_name": [
"serine/threonine kinase 9",
"cyclin-dependent kinase-like 5"
],
"prev_symbol": [
"STK9"
],
"pubmed_id": [
9721213,
16935860
],
"refseq_accession": [
"NM_003159"
],
"rgd_id": [
"RGD:2324133"
],
"status": "Approved",
"symbol": "CDKL5",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004cyn.4",
"uniprot_ids": [
"O76039"
],
"uuid": "e2ddada8-4549-4565-aacb-21ae135a19ab",
"vega_id": "OTTHUMG00000021214"
},
"NCBI": {
"id": "6792"
}
},
"entId": "CDKL5",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11411",
"entType": "Gene",
"ldhId": "135641943",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641943",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963049980000,
"agr": "HGNC:11079",
"alias_symbol": [
"NHE6",
"KIAA0267"
],
"bioparadigms_slc": "SLC9A6",
"ccds_id": [
"CCDS55504",
"CCDS44003",
"CCDS83492",
"CCDS14654"
],
"date_approved_reserved": "1999-07-30",
"date_modified": "2020-04-02",
"date_name_changed": "2016-02-25",
"ena": [
"AF030409"
],
"ensembl_gene_id": "ENSG00000198689",
"entrez_id": "10479",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:11079",
"iuphar": "objectId:953",
"location": "Xq26.3",
"location_sortable": "Xq26.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SLC9A6"
],
"mane_select": [
"ENST00000630721.3",
"NM_001379110.1"
],
"mgd_id": [
"MGI:2443511"
],
"name": "solute carrier family 9 member A6",
"omim_id": [
"300231"
],
"orphanet": 158415,
"prev_name": [
"solute carrier family 9 (sodium/hydrogen exchanger), isoform 6",
"solute carrier family 9 (sodium/hydrogen exchanger), member 6",
"solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6"
],
"pubmed_id": [
9507001
],
"refseq_accession": [
"NM_006359"
],
"rgd_id": [
"RGD:1563582"
],
"status": "Approved",
"symbol": "SLC9A6",
"ucsc_id": "uc004ezk.4",
"uniprot_ids": [
"Q92581"
],
"uuid": "b6c70e29-8831-4056-bece-f6ea1bebac3c",
"vega_id": "OTTHUMG00000022498"
},
"NCBI": {
"id": "10479"
}
},
"entId": "SLC9A6",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11079",
"entType": "Gene",
"ldhId": "135641940",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641940",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056947891765200,
"agr": "HGNC:3811",
"alias_name": [
"brain factor 1"
],
"alias_symbol": [
"HFK2",
"QIN",
"BF1",
"HFK1",
"HFK3",
"HBF-3"
],
"ccds_id": [
"CCDS9636"
],
"date_approved_reserved": "1994-12-07",
"date_modified": "2021-05-26",
"date_name_changed": "2007-05-16",
"date_symbol_changed": "2007-05-16",
"ensembl_gene_id": "ENSG00000176165",
"entrez_id": "2290",
"gene_group": [
"Forkhead boxes"
],
"gene_group_id": [
508
],
"hgnc_id": "HGNC:3811",
"location": "14q12",
"location_sortable": "14q12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000313071.7",
"NM_005249.5"
],
"mgd_id": [
"MGI:1347464"
],
"name": "forkhead box G1",
"omim_id": [
"164874"
],
"orphanet": 167854,
"prev_name": [
"forkhead box G1B",
"forkhead box G1C",
"forkhead box G1A"
],
"prev_symbol": [
"FKHL2",
"FOXG1B",
"FKHL4",
"FKH2",
"FKHL1",
"FOXG1C",
"FKHL3",
"FOXG1A"
],
"pubmed_id": [
7959731,
17260156
],
"refseq_accession": [
"NM_005249"
],
"rgd_id": [
"RGD:2619"
],
"status": "Approved",
"symbol": "FOXG1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wqe.5",
"uniprot_ids": [
"P55316"
],
"uuid": "14559109-ad8e-40f8-bf17-ebb1f1e0bd99",
"vega_id": "OTTHUMG00000140187"
},
"NCBI": {
"id": "2290"
}
},
"entId": "FOXG1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3811",
"entType": "Gene",
"ldhId": "135641939",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641939",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963120234500,
"agr": "HGNC:16266",
"alias_name": [
"thiamine transporter 2"
],
"alias_symbol": [
"THTR2"
],
"bioparadigms_slc": "SLC19A3",
"ccds_id": [
"CCDS2468"
],
"date_approved_reserved": "2001-07-19",
"date_modified": "2017-04-20",
"date_name_changed": "2016-02-17",
"ena": [
"AF271633"
],
"ensembl_gene_id": "ENSG00000135917",
"entrez_id": "80704",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:16266",
"iuphar": "objectId:1016",
"location": "2q36.3",
"location_sortable": "02q36.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000644224.2",
"NM_025243.4"
],
"mgd_id": [
"MGI:1931307"
],
"name": "solute carrier family 19 member 3",
"omim_id": [
"606152"
],
"orphanet": 118766,
"prev_name": [
"solute carrier family 19, member 3",
"solute carrier family 19 (thiamine transporter), member 3"
],
"pubmed_id": [
11136550,
15871139
],
"refseq_accession": [
"NM_025243"
],
"rgd_id": [
"RGD:1311413"
],
"status": "Approved",
"symbol": "SLC19A3",
"ucsc_id": "uc002vpi.4",
"uniprot_ids": [
"Q9BZV2"
],
"uuid": "560fc138-355e-419a-9050-d523d75f502b",
"vega_id": "OTTHUMG00000133185"
},
"NCBI": {
"id": "80704"
}
},
"entId": "SLC19A3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:16266",
"entType": "Gene",
"ldhId": "135641937",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641937",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--A"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056947152519200,
"agr": "HGNC:23287",
"alias_symbol": [
"YF13H12",
"HSCO"
],
"ccds_id": [
"CCDS12622"
],
"date_approved_reserved": "2003-12-15",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ensembl_gene_id": "ENSG00000105755",
"entrez_id": "23474",
"enzyme_id": [
"1.13.11.18"
],
"hgnc_id": "HGNC:23287",
"location": "19q13.31",
"location_sortable": "19q13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000292147.7",
"NM_014297.5"
],
"mgd_id": [
"MGI:1913321"
],
"name": "ETHE1 persulfide dioxygenase",
"omim_id": [
"608451"
],
"orphanet": 121629,
"prev_name": [
"ethylmalonic encephalopathy 1"
],
"pubmed_id": [
19136963
],
"refseq_accession": [
"NM_014297"
],
"rgd_id": [
"RGD:1311034"
],
"status": "Approved",
"symbol": "ETHE1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002owp.3",
"uniprot_ids": [
"O95571"
],
"uuid": "636414c2-a027-4641-9152-9eda9a4a0faa",
"vega_id": "OTTHUMG00000182697"
},
"NCBI": {
"id": "23474"
}
},
"entId": "ETHE1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:23287",
"entType": "Gene",
"ldhId": "135641936",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641936",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957250306000,
"agr": "HGNC:8806",
"alias_name": [
"pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial"
],
"ccds_id": [
"CCDS14192",
"CCDS55382",
"CCDS55381",
"CCDS55380"
],
"date_approved_reserved": "1989-06-30",
"date_modified": "2020-04-02",
"date_name_changed": "2019-11-26",
"ensembl_gene_id": "ENSG00000131828",
"entrez_id": "5160",
"enzyme_id": [
"1.2.4.1"
],
"gene_group": [
"Pyruvate dehydrogenase complex"
],
"gene_group_id": [
1547
],
"hgnc_id": "HGNC:8806",
"location": "Xp22.12",
"location_sortable": "Xp22.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/PDHA1"
],
"mane_select": [
"ENST00000422285.7",
"NM_000284.4"
],
"mgd_id": [
"MGI:97532"
],
"name": "pyruvate dehydrogenase E1 subunit alpha 1",
"omim_id": [
"300502"
],
"orphanet": 124161,
"prev_name": [
"pyruvate dehydrogenase (lipoamide) alpha 1",
"pyruvate dehydrogenase alpha 1"
],
"prev_symbol": [
"PDHA"
],
"refseq_accession": [
"NM_000284"
],
"rgd_id": [
"RGD:3286"
],
"status": "Approved",
"symbol": "PDHA1",
"ucsc_id": "uc011mjc.3",
"uniprot_ids": [
"P08559"
],
"uuid": "49150386-c42a-4826-bf0d-e7cb29bd23fd",
"vega_id": "OTTHUMG00000021224"
},
"NCBI": {
"id": "5160"
}
},
"entId": "PDHA1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8806",
"entType": "Gene",
"ldhId": "135641935",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641935",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---D"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056964794810400,
"agr": "HGNC:11634",
"alias_name": [
"SL3-3 enhancer factor 2",
"class B basic helix-loop-helix protein 19",
"immunoglobulin transcription factor 2"
],
"alias_symbol": [
"SEF2-1B",
"ITF2",
"bHLHb19",
"E2-2"
],
"ccds_id": [
"CCDS86672",
"CCDS77192",
"CCDS42438",
"CCDS58623",
"CCDS58624",
"CCDS58625",
"CCDS58626",
"CCDS58627",
"CCDS58628",
"CCDS82257",
"CCDS82255",
"CCDS77191",
"CCDS58629",
"CCDS58630",
"CCDS58631",
"CCDS59321",
"CCDS11960",
"CCDS86671"
],
"date_approved_reserved": "1990-10-16",
"date_modified": "2020-04-02",
"ena": [
"M74719"
],
"ensembl_gene_id": "ENSG00000196628",
"entrez_id": "6925",
"gene_group": [
"Basic helix-loop-helix proteins"
],
"gene_group_id": [
420
],
"hgnc_id": "HGNC:11634",
"location": "18q21.2",
"location_sortable": "18q21.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/TCF4"
],
"mane_select": [
"ENST00000354452.8",
"NM_001083962.2"
],
"mgd_id": [
"MGI:98506"
],
"name": "transcription factor 4",
"omim_id": [
"602272"
],
"orphanet": 158595,
"pubmed_id": [
9302263,
2308860
],
"refseq_accession": [
"NM_003199"
],
"rgd_id": [
"RGD:69271"
],
"status": "Approved",
"symbol": "TCF4",
"ucsc_id": "uc002lfz.3",
"uniprot_ids": [
"P15884"
],
"uuid": "31116aa1-aa61-42da-bb3d-7f6f2325744d",
"vega_id": "OTTHUMG00000132713"
},
"NCBI": {
"id": "6925"
}
},
"entId": "TCF4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11634",
"entType": "Gene",
"ldhId": "135641942",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641942",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "014_nuclear_ETHE1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0011229",
"preferredTitle": "Ethylmalonic encephalopathy"
}
],
"gene": "ETHE1",
"preferredTranscript": "NM_014297.5"
}
],
"ns": "014"
},
"entType": "RuleSet",
"ldhId": "135641176",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641176",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--G"
},
{
"entContent": {
"_uniqueProp": "014_nuclear_POLG",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0044970",
"preferredTitle": "Mitochondrial disease"
}
],
"gene": "POLG",
"preferredTranscript": "NM_002693.2"
}
],
"ns": "014"
},
"entType": "RuleSet",
"ldhId": "135641175",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641175",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--E"
},
{
"entContent": {
"_uniqueProp": "014_nuclear_PDHA1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0019169",
"preferredTitle": "Pyruvate dehydrogenase deficiency"
}
],
"gene": "PDHA1",
"preferredTranscript": "NM_000284.4"
}
],
"ns": "014"
},
"entType": "RuleSet",
"ldhId": "135641174",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641174",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--F"
},
{
"entContent": {
"_uniqueProp": "014_nuclear_SLC19A3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0011841",
"preferredTitle": "Biotin-responsive basal ganglia disease"
}
],
"gene": "SLC19A3",
"preferredTranscript": "NM_025243.4"
}
],
"ns": "014"
},
"entType": "RuleSet",
"ldhId": "135641173",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641173",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--F"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN029",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:03.420Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"029"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ETHE1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN029",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243099",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243099",
"modified": "2022-08-18T19:12:07.364Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju---"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN030",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:07.840Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"030"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC19A3 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN030",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243100",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243100",
"modified": "2022-08-18T19:12:11.423Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--_"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN031",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:11.889Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"031"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PDHA1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN031",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243101",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243101",
"modified": "2022-08-18T19:12:15.742Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6---"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN028",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:11:58.490Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"028"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for POLG Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN028",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243098",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243098",
"modified": "2022-08-18T19:12:02.919Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--_"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"namespace": "GN015",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines mtDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"015"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA",
"version": "1.0.0"
},
"entId": "GN015",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "015_PP5_mitochondrial",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [],
"instructionsToUse": "",
"label": "PP5",
"ns": "015",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433256",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433256",
"modified": "2022-01-19T20:31:33.145Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--I"
},
{
"entContent": {
"_uniqueProp": "015_PP4_mitochondrial",
"additionalComments": "Other causes of ETC enzyme deficiency must be excluded, to the best of current ability, by comprehensive mtDNA and nDNA sequencing. Nuclear DNA genes including ETC complex subunits, assembly factors, and translation components should be thoroughly evaluated with no pathogenic or likely pathogenic variants (present in trans if autosomal recessive inheritance) that could be causative detected. See Supplemental file for list of genes.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP4",
"ns": "015",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Decreased ETC enzyme activity (<20%) performed in a CLIA-approved (or equivalently-certified) laboratory in muscle, liver, and/or fibroblasts (for fibroblasts, must be seen in multiple unrelated probands and/or assayed in different individuals).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638272",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638272",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--A"
},
{
"entContent": {
"_uniqueProp": "015_BA1_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BA1",
"ns": "015",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Top-level haplogroup defining variants in individuals that are members of that same top-level haplogroup OR Allele frequency > 0.01 (1%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638268",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638268",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--E"
},
{
"entContent": {
"_uniqueProp": "015_PP1_mitochondrial",
"additionalComments": "Variant must not only segregate in maternal family members, but the level of heteroplasmy must also segregate with disease manifestations, where those individuals with more mild symptoms or appearing to be healthy have lower to undetectable levels of the variant and those more severely affected individuals and/or tissues have higher levels of the variant.\nThis criterion cannot be applied when a variant is present at homoplasmy in multiple family members.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP1",
"ns": "015",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in 5+ maternal family members and level of heteroplasmy segregating with disease manifestations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in 2-4 maternal family members and level of heteroplasmy segregating with disease manifestations",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638264",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638264",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxou---"
},
{
"entContent": {
"_uniqueProp": "015_BP3_mitochondrial",
"additionalComments": "There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneType": "mitochondrial",
"label": "BP3",
"ns": "015",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638261",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638261",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--_"
},
{
"entContent": {
"_uniqueProp": "015_BS4_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BS4",
"ns": "015",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family and/or segregation of disease in paternal family members",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638256",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638256",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--J"
},
{
"entContent": {
"_uniqueProp": "015_PM2_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"geneType": "mitochondrial",
"label": "PM2",
"ns": "015",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Frequency <0.00002 (0.002%, 1/50,000) from controls",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638274",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638274",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--E"
},
{
"entContent": {
"_uniqueProp": "015_BP7_mitochondrial",
"additionalComments": "Mitochondrial genes do not undergo splicing. Conservation is included in predictor algorithms used in PP3 and BP4, so conservation will be incorporated in this criterion.",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "BP7",
"ns": "015",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638271",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638271",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--A"
},
{
"entContent": {
"_uniqueProp": "015_PS2_mitochondrial",
"additionalComments": "Older sequencing techniques such as Sanger sequencing cannot reliably detect heteroplasmy levels below 30-50%. Current NGS techniques can typically detect heteroplasmy levels as low as 1.5%. It is recommended to test several tissues in the mother to fully assess for the presence and level of the mtDNA variant in question. Utilize ClinGen SVI recommendation for applying these criteria (https://clinicalgenome.org/site/assets/files/3461/ svi_proposal_for_de_novo_criteria_v1_0.pdf), the mitochondrial genome would best fit with Table 1 “phenotypic consistency” category of “phenotype consistent with gene but not highly specific.”",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PS2",
"ns": "015",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638260",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638260",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--L"
},
{
"entContent": {
"_uniqueProp": "015_PM5_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PM5",
"ns": "015",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applied per original ACMG/AMP guidelines (protein-coding genes)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0048",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same nucleotide position as previously established pathogenic variant in a rRNA/tRNA",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638254",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638254",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--D"
},
{
"entContent": {
"_uniqueProp": "015_BS3_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"geneType": "mitochondrial",
"label": "BS3",
"ns": "015",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No evidence of functional effect in cybrid studies or single fiber analysis is present (no statistically significant difference from control; mean values of <2 SD from control mean, or 50% enzyme activity compared to controls).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638253",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638253",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--I"
},
{
"entContent": {
"_uniqueProp": "015_PM3_mitochondrial",
"additionalComments": "mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"geneType": "mitochondrial",
"label": "PM3",
"ns": "015",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638250",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638250",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--K"
},
{
"entContent": {
"_uniqueProp": "015_PM1_mitochondrial",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"geneType": "mitochondrial",
"label": "PM1",
"ns": "015",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638273",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638273",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--M"
},
{
"entContent": {
"_uniqueProp": "015_PP2_mitochondrial",
"additionalComments": "mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"geneType": "mitochondrial",
"label": "PP2",
"ns": "015",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638269",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638269",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---F"
},
{
"entContent": {
"_uniqueProp": "015_PS3_mitochondrial",
"additionalComments": "The following criteria should be met to apply:\n* a biochemical deficiency must be observed in patient cell line with mtDNA variant in question.\n* whether the biochemical deficiency is transferred to mutant cybrids (in the case of enzymatic deficiency, <20% activity of control or a decrease in activity that is >2 standard deviations from control mean.\n* whether cybrid cells carry high mutant load (minimal 60%).\n * if studies have been reproduced and are consistent.",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"geneType": "mitochondrial",
"label": "PS3",
"ns": "015",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional validation is present in cybrid studies or single fiber analysis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638262",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638262",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---C"
},
{
"entContent": {
"_uniqueProp": "015_PM6_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PM6",
"ns": "015",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638257",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638257",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--K"
},
{
"entContent": {
"_uniqueProp": "015_PM4_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PM4",
"ns": "015",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applied per original ACMG/AMP guidelines",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638252",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638252",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--H"
},
{
"entContent": {
"_uniqueProp": "015_BP6_mitochondrial",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [],
"instructionsToUse": "",
"label": "BP6",
"ns": "015",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433255",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433255",
"modified": "2022-01-19T20:31:33.145Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--G"
},
{
"entContent": {
"_uniqueProp": "015_PP3_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PP3",
"ns": "015",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, etc)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638270",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638270",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--h"
},
{
"entContent": {
"_uniqueProp": "015_BP5_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP5",
"ns": "015",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Mitochondrial DNA variant found in a case with a nuclear DNA-related disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638267",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638267",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--g"
},
{
"entContent": {
"_uniqueProp": "015_PVS1_mitochondrial",
"additionalComments": "Nonsense mediated decay is not known to occur for mtDNA, however ClinGen SVI PVS1 guidelines (Abou Tayoun et al., 2018) will be utilized when applicable (see figure).",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PVS1",
"ns": "015",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638266",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638266",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---E"
},
{
"entContent": {
"_uniqueProp": "015_PS4_mitochondrial",
"additionalComments": "Individuals are defined as affected if they:\n* meet diagnostic criteria for one of the classic mitochondrial disease clinical syndromes (MELAS, MERRF, MIDD, NARP, Pearson, KSS, CPEO, CPEO plus, Leigh, Alpers, LHON, primary lactic acidosis).\n OR \n* have 1 “red flag” feature with 2 or more nonspecific features (see tables in Haas et al., 2007)\n OR \n* have 3 or more nonspecific features with lab abnormalities (see table in Haas et al., 2008).",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "PS4",
"ns": "015",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant present in ≥16 unrelated probands",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant present in ≥4 unrelated probands",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant present in 2 unrelated probands in different top-level haplogroups",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638265",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638265",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--_"
},
{
"entContent": {
"_uniqueProp": "015_BP4_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP4",
"ns": "015",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, etc)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638263",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638263",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--D"
},
{
"entContent": {
"_uniqueProp": "015_BP2_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BP2",
"ns": "015",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Other mtDNA variant is observed in individual’s mtDNA that has previously been confirmed to be pathogenic",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638259",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638259",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--f"
},
{
"entContent": {
"_uniqueProp": "015_PS1_mitochondrial",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"geneClass": [
"mRNA"
],
"geneType": "mitochondrial",
"label": "PS1",
"ns": "015",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applied per original ACMG/AMP guidelines",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638258",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638258",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--L"
},
{
"entContent": {
"_uniqueProp": "015_BP1_mitochondrial",
"additionalComments": "Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"geneType": "mitochondrial",
"label": "BP1",
"ns": "015",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638255",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638255",
"modified": "2022-01-19T20:33:35.120Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--P"
},
{
"entContent": {
"_uniqueProp": "015_BS2_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BS2",
"ns": "015",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in same tissue tested in an affected individual",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in different tissue(s) tested in an affected individual",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638251",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638251",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--G"
},
{
"entContent": {
"_uniqueProp": "015_BS1_mitochondrial",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"geneClass": [
"mRNA",
"tRNA",
"rRNA"
],
"geneType": "mitochondrial",
"label": "BS1",
"ns": "015",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency 0.005 - 0.0099 (0.5% - 0.99%)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638249",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638249",
"modified": "2021-11-05T21:07:13.444Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--C"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "015_mitochondrial",
"geneType": "mitochondrial",
"ns": "015"
},
"entType": "RuleSet",
"ldhId": "135641398",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641398",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--I"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637588",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637588",
"modified": "2023-09-29T15:16:47.750Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---C"
},
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ld": {
"Assertion": [
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Benign",
"sepioId": "LN:LA6675-8"
},
"entType": "Assertion",
"ldhId": "135642236",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642236",
"modified": null,
"rev": "_h6SHxdK--B"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Pathogenic",
"sepioId": "LN:LA6668-3"
},
"entType": "Assertion",
"ldhId": "135642233",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642233",
"modified": null,
"rev": "_h6SHxdK--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Insufficient Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642235",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642235",
"modified": null,
"rev": "_h6SHxc6--H"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642234",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642234",
"modified": null,
"rev": "_h6SHxc6--A"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Benign",
"sepioId": "LN:LA26334-5"
},
"entType": "Assertion",
"ldhId": "135642232",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642232",
"modified": null,
"rev": "_h6SHxc6--G"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Likely Pathogenic",
"sepioId": "LN:LA26332-9"
},
"entType": "Assertion",
"ldhId": "135642237",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642237",
"modified": null,
"rev": "_h6SHxdK--C"
},
{
"entContent": {
"curationActivity": "Variant Pathogenicity",
"label": "Uncertain Significance - Conflicting Evidence",
"sepioId": "LN:LA26333-7"
},
"entType": "Assertion",
"ldhId": "135642231",
"ldhIri": "https://genboree.org/cspec/Assertion/id/135642231",
"modified": null,
"rev": "_h6SHxc6--_"
}
],
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_UBE3A",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638561",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638561",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---E"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638555",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638555",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--O"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638545",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638545",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--H"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638544",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638544",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--B"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (basic Helix-Loop-Helix domain (bHLH): aa 564-617).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638539",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638539",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---C"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638536",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638536",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--A"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638534",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638534",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--K"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638532",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638532",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--J"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638529",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638529",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---A"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638520",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638520",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--B"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638510",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638510",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--J"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_SLC9A6",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638509",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638509",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--K"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 10).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638506",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638506",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--_"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638505",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638505",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--H"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638504",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638504",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy---"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638498",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638498",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--F"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638497",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638497",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--E"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638495",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638495",
"modified": "2021-11-05T21:07:13.862Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--i"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638494",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638494",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--D"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_SLC9A6",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638490",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638490",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--N"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* Methyl-DNA binding (MDB): aa 90-162; Transcriptional repression domain (TRD): aa 302-306.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638487",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638487",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--G"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638486",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638486",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--M"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_MECP2",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638483",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638483",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--C"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638477",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638477",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--F"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638474",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638474",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--C"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (Forkhead: aa 181-275).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638461",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638461",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--_"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638459",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638459",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--K"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638456",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638456",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--K"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638452",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638452",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---L"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638450",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638450",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--F"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_FOXG1",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638438",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638438",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--W"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638435",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638435",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--H"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_CDKL5",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638431",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638431",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--D"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638415",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638415",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--B"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_CDKL5",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638412",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638412",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--B"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433420",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433420",
"modified": "2022-01-19T20:31:34.350Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--L"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_SLC9A6",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC9A6"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433367",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433367",
"modified": "2022-01-19T20:31:34.054Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--J"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_MECP2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MECP2"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433339",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433339",
"modified": "2022-01-19T20:31:33.889Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--D"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433286",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433286",
"modified": "2022-01-19T20:31:33.578Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--J"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, and for canonical splice site variants predicted to result in an out-of-frame product.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.G850.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638558",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638558",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--K"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638554",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638554",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--L"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638553",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638553",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--N"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638551",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638551",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--D"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638546",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638546",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--C"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638538",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638538",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--L"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638537",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638537",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--F"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638533",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638533",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--E"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638523",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638523",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--H"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638519",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638519",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--C"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638518",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638518",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--A"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* The variant should be in the hemizygous state in the case with an alternate molecular basis for disease to be used.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638507",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638507",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--I"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638500",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638500",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--G"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638499",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638499",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--P"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638496",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638496",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--E"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638491",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638491",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--D"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638485",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638485",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--C"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638484",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638484",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--L"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638482",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638482",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--B"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638470",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638470",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--_"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638469",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638469",
"modified": "2021-11-05T21:07:13.769Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--F"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638465",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638465",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--H"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638445",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638445",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--Y"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638444",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638444",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--X"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638443",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638443",
"modified": "2021-11-05T21:07:13.638Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--N"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline and Glutaminerich region (p.58-p.86) and Proline-rich region (p.105-p.112).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638440",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638440",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---J"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638439",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638439",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--I"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638437",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638437",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--V"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638433",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638433",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--U"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638426",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638426",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---H"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638416",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638416",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--C"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) when using the NM_003159.2 transcript. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638414",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638414",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--C"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638413",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638413",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---G"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_TCF4",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433393",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433393",
"modified": "2022-01-19T20:31:34.202Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi---"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_SLC9A6",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC9A6"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433366",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433366",
"modified": "2022-01-19T20:31:34.054Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--B"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_MECP2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MECP2"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433340",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433340",
"modified": "2022-01-19T20:31:33.889Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--I"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_FOXG1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433313",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433313",
"modified": "2022-01-19T20:31:33.731Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--S"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638557",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638557",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--F"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638552",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638552",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--K"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638550",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638550",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--J"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638548",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638548",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--I"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638547",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638547",
"modified": "2021-11-05T21:07:14.050Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--F"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638543",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638543",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--M"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638540",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638540",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--H"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_TCF4",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638535",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638535",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--F"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638526",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638526",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG---"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638522",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638522",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp----"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638514",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638514",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--L"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638508",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638508",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq---"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638503",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638503",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--R"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638502",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638502",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--Q"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638501",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638501",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--F"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members. ≥5 informative meiosis .Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members. 3-4 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members. 2 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638478",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638478",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--B"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638475",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638475",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--D"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638472",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638472",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--A"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638471",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638471",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--B"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638462",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638462",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--G"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.S468.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.S469 to p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638454",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638454",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--I"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638446",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638446",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--E"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638436",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638436",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--E"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638432",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638432",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--D"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638424",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638424",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--A"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_FOXG1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433312",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433312",
"modified": "2022-01-19T20:31:33.731Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--H"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638562",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638562",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--Q"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638560",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638560",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--L"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638559",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638559",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--P"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638549",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638549",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--J"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638531",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638531",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--I"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638530",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638530",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---B"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638528",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638528",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---_"
},
{
"entContent": {
"_uniqueProp": "016_BS2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "016",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638517",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638517",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--L"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_TCF4",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638516",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638516",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--K"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638515",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638515",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--B"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638513",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638513",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--_"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638512",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638512",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--G"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638511",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638511",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--A"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638493",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638493",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--O"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638492",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638492",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--J"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638488",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638488",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--H"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.E472.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638480",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638480",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--K"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638473",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638473",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--A"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ≥2 different missense changes affecting the amino acid residue. Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Applicable to all genes as written. A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638468",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638468",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--A"
},
{
"entContent": {
"_uniqueProp": "016_PM4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "016",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene p.381-p.405).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638466",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638466",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--I"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_MECP2",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638464",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638464",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6---"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638463",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638463",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom---"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638460",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638460",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--L"
},
{
"entContent": {
"_uniqueProp": "016_PP3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638458",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638458",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC---"
},
{
"entContent": {
"_uniqueProp": "016_PP2_nuclear_FOXG1",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638457",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638457",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--J"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638453",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638453",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--H"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638447",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638447",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--Z"
},
{
"entContent": {
"_uniqueProp": "016_PM5_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "016",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638442",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638442",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--F"
},
{
"entContent": {
"_uniqueProp": "016_BA1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BA1",
"ns": "016",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638430",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638430",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--C"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638427",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638427",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--T"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638421",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638421",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--D"
},
{
"entContent": {
"_uniqueProp": "016_PM6_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "016",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638419",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638419",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--_"
},
{
"entContent": {
"_uniqueProp": "016_BS4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "016",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member, when seen in two or more families.\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n* Absent in a similarly affected family member.\n* Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638418",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638418",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2---"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638417",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638417",
"modified": "2021-11-05T21:07:13.541Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--M"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638411",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638411",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--Q"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433421",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433421",
"modified": "2022-01-19T20:31:34.350Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--E"
},
{
"entContent": {
"_uniqueProp": "016_PP5_nuclear_TCF4",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433394",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433394",
"modified": "2022-01-19T20:31:34.202Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--K"
},
{
"entContent": {
"_uniqueProp": "016_BP6_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "016",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433285",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433285",
"modified": "2022-01-19T20:31:33.578Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--C"
},
{
"entContent": {
"_uniqueProp": "016_PM2_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "016",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638566",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638566",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2---"
},
{
"entContent": {
"_uniqueProp": "016_PM1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "016",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* 3’ cysteine binding site: aa 820.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638565",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638565",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---F"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638564",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638564",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--M"
},
{
"entContent": {
"_uniqueProp": "016_BP7_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "016",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638563",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638563",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--R"
},
{
"entContent": {
"_uniqueProp": "016_PP1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "016",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n* ≥5 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n* 3-4 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n* 2 informative meiosis.\n* Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638556",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638556",
"modified": "2022-01-19T20:33:35.556Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--E"
},
{
"entContent": {
"_uniqueProp": "016_PM3_nuclear_UBE3A",
"additionalComments": "Do not use",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "016",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638542",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638542",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--G"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_UBE3A",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0007113"
],
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638541",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638541",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---D"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638527",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638527",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--_"
},
{
"entContent": {
"_uniqueProp": "016_BP2_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "016",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n* BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638525",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638525",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--E"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638524",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638524",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--D"
},
{
"entContent": {
"_uniqueProp": "016_BP1_nuclear_TCF4",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0012589"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "016",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638521",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638521",
"modified": "2021-11-05T21:07:13.956Z",
"modifier": "genbadmin",
"rev": "_h6SHxoa--j"
},
{
"entContent": {
"_uniqueProp": "016_BS1_nuclear_SLC9A6",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010278"
],
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "016",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638489",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638489",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--I"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638481",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638481",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--L"
},
{
"entContent": {
"_uniqueProp": "016_PS4_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "016",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638479",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638479",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--J"
},
{
"entContent": {
"_uniqueProp": "016_PS3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638476",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638476",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--E"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_MECP2",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0010726"
],
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638467",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638467",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--_"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638455",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638455",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--J"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638451",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638451",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--b"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.\n* Inframe expansions or deletions in FOXG1 repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638449",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638449",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--a"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638448",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638448",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--G"
},
{
"entContent": {
"_uniqueProp": "016_BS3_nuclear_FOXG1",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"disease": [
"MONDO:0100040"
],
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "016",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638441",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638441",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---K"
},
{
"entContent": {
"_uniqueProp": "016_PP4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "016",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638434",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638434",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--G"
},
{
"entContent": {
"_uniqueProp": "016_BP5_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "016",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638429",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638429",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---I"
},
{
"entContent": {
"_uniqueProp": "016_PVS1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "016",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* Do not use PVS1 for truncating variants in CDKL5 Cterminus (exons 19-21, or after p.P904) when using the historically used transcript (NM_003159.2). PVS1 is applicable up to p.R948 when using the major brain isoform which has an alternative C-terminus (NM_001323289.2), for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0020",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.R948 (when using the major brain isoform, NM_001323289.2) and for canonical splice site variants that flank exon 17 (in-frame exon).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638428",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638428",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--B"
},
{
"entContent": {
"_uniqueProp": "016_BP4_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "016",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638425",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638425",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--F"
},
{
"entContent": {
"_uniqueProp": "016_BP3_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "016",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638423",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638423",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--S"
},
{
"entContent": {
"_uniqueProp": "016_PS2_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "016",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638422",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638422",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--E"
},
{
"entContent": {
"_uniqueProp": "016_PS1_nuclear_CDKL5",
"additionalComments": "",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"disease": [
"MONDO:0100039"
],
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "016",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "135638420",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/135638420",
"modified": "2022-01-19T20:33:35.555Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--R"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100039",
"lbl": "CDKL5 disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/202"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100039"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000594"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0017656"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:32:48Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
}
],
"comments": [
"Subtypes of the heterogeneous, eponymously named Early Infantile Epileptic Encephalopathy, Atypical Rett Syndrome, West Syndrome are caused by mutations in the gene CDKL5. The common and most penetrant phenotype shared among these disease entities is early onset epilepsy, progressive microcephaly, dysmorphic facial features, and intellectual disability, with stereotypic hand movements, respiratory impairment with breath holding and hyperventilation having variable phenotypic expressivity. (https://orcid.org/0000-0002-6733-369X)"
],
"definition": {
"val": "A monogenic disease that has material basis in mutation in the CDKL5 gene.",
"xrefs": [
"PMID:21154482",
"PMID:22872100",
"PMID:27080038",
"PMID:27528505"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "CDKL5 Deficiency Disorder",
"xrefs": [
"NORD:904"
]
},
{
"pred": "hasExactSynonym",
"val": "CDKL5 disorder"
},
{
"pred": "hasExactSynonym",
"val": "CDKL5 inherited genetic disease",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "inherited genetic disease caused by mutation in CDKL5",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CDKL5",
"xrefs": [
"GARD:0012173"
]
},
{
"pred": "hasRelatedSynonym",
"val": "CDKL5-related disorder",
"xrefs": [
"GARD:0012173"
]
}
],
"xrefs": [
{
"val": "NORD:904"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100039",
"name": "CDKL5 disorder",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0100039",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100039",
"entType": "Disease",
"ldhId": "135642215",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642215",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjS---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012589",
"lbl": "Pitt-Hopkins syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012589"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/pitt_hopkins_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/4372/pitt-hopkins-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/2040786134"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/370910"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C537403"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702344008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1970431"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060488"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129872"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_2896"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/610954"
}
],
"definition": {
"val": "Pitt-Hopkins syndrome (PHS) is characterized by the association of intellectual deficit, characteristic facial dysmorphism and problems of abnormal and irregular breathing.",
"xrefs": [
"Orphanet:2896"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Pitt-Hopkins syndrome",
"xrefs": [
"DOID:0060488",
"MONDO:Lexical",
"NCIT:C129872",
"OMIM:610954",
"Orphanet:2896",
"icd11.foundation:2040786134"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PTHS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Pitt Hopkins syndrome",
"xrefs": [
"GARD:0004372"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, Severe epileptic, with autonomic dysfunction"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, Syndromal, with intermittent hyperventilation"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea",
"xrefs": [
"GARD:0004372"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, Syndromal, with intermittent hyperventilation"
}
],
"xrefs": [
{
"val": "DOID:0060488"
},
{
"val": "GARD:4372"
},
{
"val": "ICD9:758.5"
},
{
"val": "MEDGEN:370910"
},
{
"val": "MESH:C537403"
},
{
"val": "NCIT:C129872"
},
{
"val": "NORD:1921"
},
{
"val": "OMIM:610954"
},
{
"val": "Orphanet:2896"
},
{
"val": "SCTID:702344008"
},
{
"val": "UMLS:C1970431"
},
{
"val": "icd11.foundation:2040786134"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012589",
"name": "Pitt-Hopkins syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0012589",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012589",
"entType": "Disease",
"ldhId": "135642214",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642214",
"modified": "2025-10-07T15:44:46.251Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Ws_G---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007113",
"lbl": "Angelman syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3941"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007113"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/angelman_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005027"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019040"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10049004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1106558408"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/58144"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C531619"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D017204"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/76880004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0162635"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/Q93.51"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1932"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C75462"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_72"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/105830"
}
],
"definition": {
"val": "A neurogenetic disorder characterized by severe intellectual deficit and distinct facial dysmorphic features.",
"xrefs": [
"Orphanet:72",
"https://orcid.org/0000-0001-5208-3432"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Angelman syndrome",
"xrefs": [
"DOID:1932",
"ICD10CM:Q93.51",
"MONDO:Lexical",
"NCIT:C75462",
"OMIM:105830",
"Orphanet:72",
"icd11.foundation:1106558408"
]
},
{
"pred": "hasExactSynonym",
"val": "Angelman’s syndrome",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome",
"xrefs": [
"DOID:1932"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "puppetlike syndrome",
"xrefs": [
"DOID:1932"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Angelman syndrome (Type 1)",
"xrefs": [
"DECIPHER:4"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Angelman syndrome (Type 2)",
"xrefs": [
"DECIPHER:54"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "AS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman syndrome chromosome region"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome (formerly)",
"xrefs": [
"GARD:0005810"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome, formerly"
}
],
"xrefs": [
{
"val": "DECIPHER:4"
},
{
"val": "DECIPHER:54"
},
{
"val": "DOID:1932"
},
{
"val": "GARD:5810"
},
{
"val": "ICD10CM:Q93.51"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:58144"
},
{
"val": "MESH:C531619"
},
{
"val": "MESH:D017204"
},
{
"val": "MedDRA:10049004"
},
{
"val": "NANDO:1200686"
},
{
"val": "NANDO:2200960"
},
{
"val": "NCIT:C75462"
},
{
"val": "NORD:782"
},
{
"val": "OMIM:105830"
},
{
"val": "Orphanet:72"
},
{
"val": "SCTID:76880004"
},
{
"val": "UMLS:C0162635"
},
{
"val": "icd11.foundation:1106558408"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007113",
"name": "Angelman syndrome"
},
"entId": "MONDO:0007113",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007113",
"entType": "Disease",
"ldhId": "135642213",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642213",
"modified": "2025-10-07T15:43:23.289Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7VarW---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010278",
"lbl": "Christianson syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010278"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/christianson_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/intellectual_developmental_disorder_x_linked_syndromic_christianson_type"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015159"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0016612"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10572/christianson-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/394455"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C567484"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702354007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2678194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060825"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_85278"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/300243"
}
],
"definition": {
"val": "A very rare form of syndromic intellectual deficit characterized by microcephaly, severe developmental delay or regression, hypotonia, abnormal movements, and early-onset seizures.",
"xrefs": [
"Orphanet:85278"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Christianson syndrome",
"xrefs": [
"DOID:0060825",
"Orphanet:85278"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MRXSCH",
"xrefs": [
"DOID:0060825",
"MONDO:Lexical",
"OMIM:300243"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked Angelman-like syndrome",
"xrefs": [
"DOID:0060825",
"Orphanet:85278"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked intellectual disability, South African type",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked intellectual disability-craniofacial dysmorphism-epilepsy-ophthalmoplegia-cerebellar atrophy syndrome",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"val": "intellectual developmental disorder, X-linked syndromic, Christianson type"
},
{
"pred": "hasExactSynonym",
"val": "intellectual disability, X-linked syndromic, Christianson type"
},
{
"pred": "hasExactSynonym",
"val": "intellectual disability, microcephaly, epilepsy, and ataxia syndrome"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked syndromic, Christianson type",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, microcephaly, epilepsy, and ataxia syndrome",
"xrefs": [
"DOID:0060825",
"OMIM:300243"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman-like syndrome X-linked",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman-like syndrome, X-linked"
},
{
"pred": "hasRelatedSynonym",
"val": "MRXS Christianson",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "X-linked intellectual disability - craniofacial dysmorphism - epilepsy - ophthalmoplegia - cerebellar atrophy",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability X-linked syndromic Christianson type",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability microcephaly epilepsy and ataxia syndrome",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked, syndromic, Christianson type",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked, syndromic, Christianson type",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0060825"
},
{
"val": "GARD:10572"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:394455"
},
{
"val": "MESH:C567484"
},
{
"val": "OMIM:300243"
},
{
"val": "Orphanet:85278"
},
{
"val": "SCTID:702354007"
},
{
"val": "UMLS:C2678194"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010278",
"name": "Christianson syndrome",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0010278",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010278",
"entType": "Disease",
"ldhId": "135642212",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642212",
"modified": "2025-10-07T15:44:09.019Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WHly---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010726",
"lbl": "Rett syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010726"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rett_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0017656"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10039000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/201200685"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/48441"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D015518"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/68618008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0035372"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1206"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C75488"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_778"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/312750"
}
],
"definition": {
"val": "A severe neurodevelopmental disorder affecting the central nervous system.",
"xrefs": [
"Orphanet:778"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "RTS",
"xrefs": [
"OMIM:312750"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "RTT",
"xrefs": [
"MONDO:Lexical",
"OMIM:312750"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome",
"xrefs": [
"DOID:1206",
"MONDO:Lexical",
"NCIT:C75488",
"OMIM:312750",
"Orphanet:778"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, atypical, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, preserved speech variant, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett's disorder",
"xrefs": [
"DOID:1206"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett’s disease",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebroatrophic hyperammonemia",
"xrefs": [
"DOID:1206"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, Zappella variant"
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, atypical"
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, preserved speech variant"
},
{
"pred": "hasRelatedSynonym",
"val": "autism, dementia, ataxia, and loss of purposeful hand use"
}
],
"xrefs": [
{
"val": "DOID:1206"
},
{
"val": "GARD:5696"
},
{
"val": "ICD9:330.8"
},
{
"val": "MEDGEN:48441"
},
{
"val": "MESH:D015518"
},
{
"val": "MedDRA:10039000"
},
{
"val": "NANDO:1200603"
},
{
"val": "NANDO:1200604"
},
{
"val": "NANDO:2100219"
},
{
"val": "NANDO:2200825"
},
{
"val": "NCIT:C75488"
},
{
"val": "NORD:1666"
},
{
"val": "OMIM:312750"
},
{
"val": "Orphanet:778"
},
{
"val": "SCTID:68618008"
},
{
"val": "UMLS:C0035372"
},
{
"val": "icd11.foundation:201200685"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010726",
"name": "Rett syndrome",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0010726",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010726",
"entType": "Disease",
"ldhId": "135642210",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642210",
"modified": "2025-10-07T15:44:17.321Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WPjK---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100040",
"lbl": "FOXG1 disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4069"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7850"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100040"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/foxg1_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/foxg1_syndrome_due_to_intragenic_alteration"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rett_syndrome_congenital_variant"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T19:29:48Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#broadMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/F84.8"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1842594"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5681589"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C176903"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_561854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_598164"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/613454"
}
],
"comments": [
"Subtypes of the heterogeneous, eponymously named Congenital variant of Rett Syndrome, and Atypical Rett Syndrome are caused by mutations in the gene FOXG1. The common and most penetrant phenotype shared among these disease entities is neurodevelopmental impairment present in early infancy, progressive microcephaly, and MRI of the brain showing reduced myelinization and/or abnormal corpus callosum. Stereotypic hand movements, epilepsy, and abnormal breathing can have variable phenotypic expressivity. (https://orcid.org/0000-0002-6733-369X)"
],
"definition": {
"val": "A monogenic disease that has material basis in mutation in the FOXG1 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "FOXG1 disorder"
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 inherited genetic disease",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 syndrome",
"xrefs": [
"MONDO:0035383"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 syndrome due to intragenic alteration",
"xrefs": [
"MONDO:0035713"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1-related epileptic-dyskinetic encephalopathy",
"xrefs": [
"Orphanet:561854"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, congenital variant",
"xrefs": [
"MONDO:0013270",
"NCIT:C176903",
"OMIM:613454"
]
},
{
"pred": "hasExactSynonym",
"val": "inherited genetic disease caused by mutation in FOXG1"
}
],
"xrefs": [
{
"val": "ICD10CM:F84.8"
},
{
"val": "MEDGEN:1842594"
},
{
"val": "NCIT:C176903"
},
{
"val": "OMIM:613454"
},
{
"val": "Orphanet:561854"
},
{
"val": "Orphanet:598164"
},
{
"val": "UMLS:C5681589"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100040",
"name": "FOXG1 disorder",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0100040",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100040",
"entType": "Disease",
"ldhId": "135642211",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642211",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFji---"
}
],
"EvidenceCategory": [
{
"entContent": {
"label": "Other Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642490",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642490",
"modified": null,
"rev": "_h6SHxqy---"
},
{
"entContent": {
"label": "Computational And Predictive Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642487",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642487",
"modified": null,
"rev": "_h6SHxr---E"
},
{
"entContent": {
"label": "Population Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642486",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642486",
"modified": null,
"rev": "_h6SHxrS--B"
},
{
"entContent": {
"label": "Other Database",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642489",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642489",
"modified": null,
"rev": "_h6SHxqu---"
},
{
"entContent": {
"label": "De novo Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642492",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642492",
"modified": null,
"rev": "_h6SHxqy--_"
},
{
"entContent": {
"label": "Functional Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642491",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642491",
"modified": null,
"rev": "_h6SHxr---G"
},
{
"entContent": {
"label": "Allelic Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642488",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642488",
"modified": null,
"rev": "_h6SHxr---F"
},
{
"entContent": {
"label": "Segregation Data",
"sepioId": ""
},
"entType": "EvidenceCategory",
"ldhId": "135642485",
"ldhIri": "https://genboree.org/cspec/EvidenceCategory/id/135642485",
"modified": null,
"rev": "_h6SHxr---D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056944354918400,
"agr": "HGNC:11411",
"alias_symbol": [
"EIEE2",
"CFAP247"
],
"ccds_id": [
"CCDS14186",
"CCDS83458"
],
"date_approved_reserved": "1997-10-27",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-07",
"date_symbol_changed": "2002-11-29",
"ena": [
"Y15057"
],
"ensembl_gene_id": "ENSG00000008086",
"entrez_id": "6792",
"gene_group": [
"Cyclin dependent kinases",
"Cilia and flagella associated"
],
"gene_group_id": [
496,
1491
],
"hgnc_id": "HGNC:11411",
"iuphar": "objectId:1986",
"location": "Xp22.13",
"location_sortable": "Xp22.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/CDKL5"
],
"mane_select": [
"ENST00000623535.2",
"NM_001323289.2"
],
"mgd_id": [
"MGI:1278336"
],
"name": "cyclin dependent kinase like 5",
"omim_id": [
"300203"
],
"orphanet": 119297,
"prev_name": [
"serine/threonine kinase 9",
"cyclin-dependent kinase-like 5"
],
"prev_symbol": [
"STK9"
],
"pubmed_id": [
9721213,
16935860
],
"refseq_accession": [
"NM_003159"
],
"rgd_id": [
"RGD:2324133"
],
"status": "Approved",
"symbol": "CDKL5",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004cyn.4",
"uniprot_ids": [
"O76039"
],
"uuid": "e2ddada8-4549-4565-aacb-21ae135a19ab",
"vega_id": "OTTHUMG00000021214"
},
"NCBI": {
"id": "6792"
}
},
"entId": "CDKL5",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11411",
"entType": "Gene",
"ldhId": "135641943",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641943",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963049980000,
"agr": "HGNC:11079",
"alias_symbol": [
"NHE6",
"KIAA0267"
],
"bioparadigms_slc": "SLC9A6",
"ccds_id": [
"CCDS55504",
"CCDS44003",
"CCDS83492",
"CCDS14654"
],
"date_approved_reserved": "1999-07-30",
"date_modified": "2020-04-02",
"date_name_changed": "2016-02-25",
"ena": [
"AF030409"
],
"ensembl_gene_id": "ENSG00000198689",
"entrez_id": "10479",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:11079",
"iuphar": "objectId:953",
"location": "Xq26.3",
"location_sortable": "Xq26.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SLC9A6"
],
"mane_select": [
"ENST00000630721.3",
"NM_001379110.1"
],
"mgd_id": [
"MGI:2443511"
],
"name": "solute carrier family 9 member A6",
"omim_id": [
"300231"
],
"orphanet": 158415,
"prev_name": [
"solute carrier family 9 (sodium/hydrogen exchanger), isoform 6",
"solute carrier family 9 (sodium/hydrogen exchanger), member 6",
"solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6"
],
"pubmed_id": [
9507001
],
"refseq_accession": [
"NM_006359"
],
"rgd_id": [
"RGD:1563582"
],
"status": "Approved",
"symbol": "SLC9A6",
"ucsc_id": "uc004ezk.4",
"uniprot_ids": [
"Q92581"
],
"uuid": "b6c70e29-8831-4056-bece-f6ea1bebac3c",
"vega_id": "OTTHUMG00000022498"
},
"NCBI": {
"id": "10479"
}
},
"entId": "SLC9A6",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11079",
"entType": "Gene",
"ldhId": "135641940",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641940",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056966728384500,
"agr": "HGNC:12496",
"alias_name": [
"Angelman syndrome"
],
"alias_symbol": [
"AS",
"ANCR",
"E6-AP",
"FLJ26981"
],
"ccds_id": [
"CCDS45192",
"CCDS86436",
"CCDS32177",
"CCDS45191"
],
"date_approved_reserved": "1993-10-21",
"date_modified": "2021-05-26",
"date_name_changed": "2008-07-31",
"ena": [
"AF002224"
],
"ensembl_gene_id": "ENSG00000114062",
"entrez_id": "7337",
"enzyme_id": [
"2.3.2.26"
],
"gene_group": [
"HECT domain containing"
],
"gene_group_id": [
1959
],
"hgnc_id": "HGNC:12496",
"location": "15q11.2",
"location_sortable": "15q11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"NGRL, Manchester LOVD|http://ngrl.manchester.ac.uk/LOVDv.2.0/home.php?select_db=UBE3A",
"LRG_15|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_15.xml"
],
"mane_select": [
"ENST00000648336.2",
"NM_130839.5"
],
"mgd_id": [
"MGI:105098"
],
"name": "ubiquitin protein ligase E3A",
"omim_id": [
"601623"
],
"orphanet": 120365,
"prev_name": [
"human papilloma virus E6-associated protein"
],
"prev_symbol": [
"EPVE6AP",
"HPVE6A"
],
"pubmed_id": [
8221889
],
"refseq_accession": [
"NM_000462"
],
"rgd_id": [
"RGD:1306361"
],
"status": "Approved",
"symbol": "UBE3A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc059gvn.1",
"uniprot_ids": [
"Q05086"
],
"uuid": "dce8245d-bf9e-41fa-b4f2-e2a570703193",
"vega_id": "OTTHUMG00000171548"
},
"NCBI": {
"id": "7337"
}
},
"entId": "UBE3A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12496",
"entType": "Gene",
"ldhId": "135641941",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641941",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---H"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056953001476000,
"agr": "HGNC:6990",
"ccds_id": [
"CCDS14741",
"CCDS48193"
],
"date_approved_reserved": "1996-09-03",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-13",
"ena": [
"AF158180"
],
"ensembl_gene_id": "ENSG00000169057",
"entrez_id": "4204",
"gene_group": [
"Methyl-CpG binding domain containing"
],
"gene_group_id": [
1025
],
"hgnc_id": "HGNC:6990",
"location": "Xq28",
"location_sortable": "Xq28",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"RettBASE|http://mecp2.chw.edu.au/",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/MECP2",
"LRG_764|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_764.xml"
],
"mane_select": [
"ENST00000453960.7",
"NM_001110792.2"
],
"mgd_id": [
"MGI:99918"
],
"name": "methyl-CpG binding protein 2",
"omim_id": [
"300005"
],
"orphanet": 123186,
"prev_name": [
"mental retardation, X-linked 16",
"mental retardation, X-linked 79",
"Rett syndrome",
"methyl CpG binding protein 2 (Rett syndrome)",
"methyl CpG binding protein 2"
],
"prev_symbol": [
"RTT",
"MRX16",
"MRX79"
],
"pubmed_id": [
1606614,
10508514
],
"refseq_accession": [
"NM_004992"
],
"rgd_id": [
"RGD:3075"
],
"status": "Approved",
"symbol": "MECP2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004fjv.3",
"uniprot_ids": [
"P51608"
],
"uuid": "c911c5cc-315e-4631-bcdd-8627c7cc337c",
"vega_id": "OTTHUMG00000024229"
},
"NCBI": {
"id": "4202"
}
},
"entId": "MECP2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6990",
"entType": "Gene",
"ldhId": "135641938",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641938",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056947152519200,
"agr": "HGNC:23287",
"alias_symbol": [
"YF13H12",
"HSCO"
],
"ccds_id": [
"CCDS12622"
],
"date_approved_reserved": "2003-12-15",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ensembl_gene_id": "ENSG00000105755",
"entrez_id": "23474",
"enzyme_id": [
"1.13.11.18"
],
"hgnc_id": "HGNC:23287",
"location": "19q13.31",
"location_sortable": "19q13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000292147.7",
"NM_014297.5"
],
"mgd_id": [
"MGI:1913321"
],
"name": "ETHE1 persulfide dioxygenase",
"omim_id": [
"608451"
],
"orphanet": 121629,
"prev_name": [
"ethylmalonic encephalopathy 1"
],
"pubmed_id": [
19136963
],
"refseq_accession": [
"NM_014297"
],
"rgd_id": [
"RGD:1311034"
],
"status": "Approved",
"symbol": "ETHE1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002owp.3",
"uniprot_ids": [
"O95571"
],
"uuid": "636414c2-a027-4641-9152-9eda9a4a0faa",
"vega_id": "OTTHUMG00000182697"
},
"NCBI": {
"id": "23474"
}
},
"entId": "ETHE1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:23287",
"entType": "Gene",
"ldhId": "135641936",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641936",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957250306000,
"agr": "HGNC:8806",
"alias_name": [
"pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial"
],
"ccds_id": [
"CCDS14192",
"CCDS55382",
"CCDS55381",
"CCDS55380"
],
"date_approved_reserved": "1989-06-30",
"date_modified": "2020-04-02",
"date_name_changed": "2019-11-26",
"ensembl_gene_id": "ENSG00000131828",
"entrez_id": "5160",
"enzyme_id": [
"1.2.4.1"
],
"gene_group": [
"Pyruvate dehydrogenase complex"
],
"gene_group_id": [
1547
],
"hgnc_id": "HGNC:8806",
"location": "Xp22.12",
"location_sortable": "Xp22.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/PDHA1"
],
"mane_select": [
"ENST00000422285.7",
"NM_000284.4"
],
"mgd_id": [
"MGI:97532"
],
"name": "pyruvate dehydrogenase E1 subunit alpha 1",
"omim_id": [
"300502"
],
"orphanet": 124161,
"prev_name": [
"pyruvate dehydrogenase (lipoamide) alpha 1",
"pyruvate dehydrogenase alpha 1"
],
"prev_symbol": [
"PDHA"
],
"refseq_accession": [
"NM_000284"
],
"rgd_id": [
"RGD:3286"
],
"status": "Approved",
"symbol": "PDHA1",
"ucsc_id": "uc011mjc.3",
"uniprot_ids": [
"P08559"
],
"uuid": "49150386-c42a-4826-bf0d-e7cb29bd23fd",
"vega_id": "OTTHUMG00000021224"
},
"NCBI": {
"id": "5160"
}
},
"entId": "PDHA1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8806",
"entType": "Gene",
"ldhId": "135641935",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641935",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---D"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957870014500,
"agr": "HGNC:9179",
"alias_symbol": [
"POLG1",
"POLGA"
],
"ccds_id": [
"CCDS10350"
],
"curator_notes": [
"[Khan et al](https://www.ncbi.nlm.nih.gov/pubmed/32138667) reports that this complex locus also contains a second alternate reading frame"
],
"date_approved_reserved": "1992-02-06",
"date_modified": "2021-04-13",
"date_name_changed": "2016-07-11",
"ena": [
"X98093"
],
"ensembl_gene_id": "ENSG00000140521",
"entrez_id": "5428",
"gene_group": [
"DNA polymerases",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
535,
1691
],
"hgnc_id": "HGNC:9179",
"location": "15q26.1",
"location_sortable": "15q26.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_765|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_765.xml"
],
"mane_select": [
"ENST00000268124.11",
"NM_002693.3"
],
"mgd_id": [
"MGI:1196389"
],
"name": "DNA polymerase gamma, catalytic subunit",
"omim_id": [
"174763"
],
"orphanet": 117925,
"prev_name": [
"polymerase (DNA directed), gamma",
"polymerase (DNA) gamma, catalytic subunit"
],
"pubmed_id": [
9465903,
32138667
],
"refseq_accession": [
"NM_002693"
],
"rgd_id": [
"RGD:620057"
],
"status": "Approved",
"symbol": "POLG",
"ucsc_id": "uc002bns.5",
"uniprot_ids": [
"P54098"
],
"uuid": "3d221088-ac02-4bc9-98bf-3f9d97e8d9c9",
"vega_id": "OTTHUMG00000149646"
},
"NCBI": {
"id": "5428"
}
},
"entId": "POLG",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9179",
"entType": "Gene",
"ldhId": "135641934",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641934",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--C"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056964794810400,
"agr": "HGNC:11634",
"alias_name": [
"SL3-3 enhancer factor 2",
"class B basic helix-loop-helix protein 19",
"immunoglobulin transcription factor 2"
],
"alias_symbol": [
"SEF2-1B",
"ITF2",
"bHLHb19",
"E2-2"
],
"ccds_id": [
"CCDS86672",
"CCDS77192",
"CCDS42438",
"CCDS58623",
"CCDS58624",
"CCDS58625",
"CCDS58626",
"CCDS58627",
"CCDS58628",
"CCDS82257",
"CCDS82255",
"CCDS77191",
"CCDS58629",
"CCDS58630",
"CCDS58631",
"CCDS59321",
"CCDS11960",
"CCDS86671"
],
"date_approved_reserved": "1990-10-16",
"date_modified": "2020-04-02",
"ena": [
"M74719"
],
"ensembl_gene_id": "ENSG00000196628",
"entrez_id": "6925",
"gene_group": [
"Basic helix-loop-helix proteins"
],
"gene_group_id": [
420
],
"hgnc_id": "HGNC:11634",
"location": "18q21.2",
"location_sortable": "18q21.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/TCF4"
],
"mane_select": [
"ENST00000354452.8",
"NM_001083962.2"
],
"mgd_id": [
"MGI:98506"
],
"name": "transcription factor 4",
"omim_id": [
"602272"
],
"orphanet": 158595,
"pubmed_id": [
9302263,
2308860
],
"refseq_accession": [
"NM_003199"
],
"rgd_id": [
"RGD:69271"
],
"status": "Approved",
"symbol": "TCF4",
"ucsc_id": "uc002lfz.3",
"uniprot_ids": [
"P15884"
],
"uuid": "31116aa1-aa61-42da-bb3d-7f6f2325744d",
"vega_id": "OTTHUMG00000132713"
},
"NCBI": {
"id": "6925"
}
},
"entId": "TCF4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11634",
"entType": "Gene",
"ldhId": "135641942",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641942",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--B"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056947891765200,
"agr": "HGNC:3811",
"alias_name": [
"brain factor 1"
],
"alias_symbol": [
"HFK2",
"QIN",
"BF1",
"HFK1",
"HFK3",
"HBF-3"
],
"ccds_id": [
"CCDS9636"
],
"date_approved_reserved": "1994-12-07",
"date_modified": "2021-05-26",
"date_name_changed": "2007-05-16",
"date_symbol_changed": "2007-05-16",
"ensembl_gene_id": "ENSG00000176165",
"entrez_id": "2290",
"gene_group": [
"Forkhead boxes"
],
"gene_group_id": [
508
],
"hgnc_id": "HGNC:3811",
"location": "14q12",
"location_sortable": "14q12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000313071.7",
"NM_005249.5"
],
"mgd_id": [
"MGI:1347464"
],
"name": "forkhead box G1",
"omim_id": [
"164874"
],
"orphanet": 167854,
"prev_name": [
"forkhead box G1B",
"forkhead box G1C",
"forkhead box G1A"
],
"prev_symbol": [
"FKHL2",
"FOXG1B",
"FKHL4",
"FKH2",
"FKHL1",
"FOXG1C",
"FKHL3",
"FOXG1A"
],
"pubmed_id": [
7959731,
17260156
],
"refseq_accession": [
"NM_005249"
],
"rgd_id": [
"RGD:2619"
],
"status": "Approved",
"symbol": "FOXG1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wqe.5",
"uniprot_ids": [
"P55316"
],
"uuid": "14559109-ad8e-40f8-bf17-ebb1f1e0bd99",
"vega_id": "OTTHUMG00000140187"
},
"NCBI": {
"id": "2290"
}
},
"entId": "FOXG1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3811",
"entType": "Gene",
"ldhId": "135641939",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641939",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056963120234500,
"agr": "HGNC:16266",
"alias_name": [
"thiamine transporter 2"
],
"alias_symbol": [
"THTR2"
],
"bioparadigms_slc": "SLC19A3",
"ccds_id": [
"CCDS2468"
],
"date_approved_reserved": "2001-07-19",
"date_modified": "2017-04-20",
"date_name_changed": "2016-02-17",
"ena": [
"AF271633"
],
"ensembl_gene_id": "ENSG00000135917",
"entrez_id": "80704",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:16266",
"iuphar": "objectId:1016",
"location": "2q36.3",
"location_sortable": "02q36.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000644224.2",
"NM_025243.4"
],
"mgd_id": [
"MGI:1931307"
],
"name": "solute carrier family 19 member 3",
"omim_id": [
"606152"
],
"orphanet": 118766,
"prev_name": [
"solute carrier family 19, member 3",
"solute carrier family 19 (thiamine transporter), member 3"
],
"pubmed_id": [
11136550,
15871139
],
"refseq_accession": [
"NM_025243"
],
"rgd_id": [
"RGD:1311413"
],
"status": "Approved",
"symbol": "SLC19A3",
"ucsc_id": "uc002vpi.4",
"uniprot_ids": [
"Q9BZV2"
],
"uuid": "560fc138-355e-419a-9050-d523d75f502b",
"vega_id": "OTTHUMG00000133185"
},
"NCBI": {
"id": "80704"
}
},
"entId": "SLC19A3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:16266",
"entType": "Gene",
"ldhId": "135641937",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641937",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "016_nuclear_TCF4",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0012589",
"preferredTitle": "Pitt-Hopkins syndrome"
}
],
"gene": "TCF4",
"preferredTranscript": "NM_001083962.1"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641462",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641462",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--J"
},
{
"entContent": {
"_uniqueProp": "016_nuclear_MECP2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0010726",
"preferredTitle": "Rett syndrome"
}
],
"gene": "MECP2",
"preferredTranscript": "NM_004992.3"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641460",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641460",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--K"
},
{
"entContent": {
"_uniqueProp": "016_nuclear_FOXG1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100040",
"preferredTitle": "FOXG1 disorder"
}
],
"gene": "FOXG1",
"preferredTranscript": "NM_005249.4"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641459",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641459",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--H"
},
{
"entContent": {
"_uniqueProp": "016_nuclear_CDKL5",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100039",
"preferredTitle": "CDKL5 disorder"
}
],
"gene": "CDKL5",
"preferredTranscript": "NM_001323289.2"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641458",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641458",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--I"
},
{
"entContent": {
"_uniqueProp": "016_nuclear_SLC9A6",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0010278",
"preferredTitle": "Christianson syndrome"
}
],
"gene": "SLC9A6",
"preferredTranscript": "NM_006359.2"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641461",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641461",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--J"
},
{
"entContent": {
"_uniqueProp": "016_nuclear_UBE3A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0007113",
"preferredTitle": "Angelman syndrome"
}
],
"gene": "UBE3A",
"preferredTranscript": "NM_130838.2"
}
],
"ns": "016"
},
"entType": "RuleSet",
"ldhId": "135641463",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/135641463",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--K"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2023-05-09T17:23:41.958Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN033",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:21.126Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:04.208Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:35.379Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:44.472Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:23:41.958Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"033"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN033",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243103",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243103",
"modified": "2023-09-29T15:16:49.367Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---E"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:22:58.500Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN032",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:17.106Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:24:55.246Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:16:57.373Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:28.132Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:22:58.500Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"032"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN032",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243102",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243102",
"modified": "2023-09-29T15:16:49.280Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--V"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:47.151Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN035",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:29.035Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:49.658Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:49.295Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:06.342Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:47.151Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"035"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN035",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243105",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243105",
"modified": "2023-09-29T15:16:49.547Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--K"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:23.860Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN037",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:36.966Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:25:24.952Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-01T12:01:42.805Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-04T16:31:30.362Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:27.074Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:23.860Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-02-09T19:15:05.530Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"037"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0",
"version": "4.0.0",
"versioned": true
},
"entId": "GN037",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243107",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243107",
"modified": "2023-09-29T15:16:49.726Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--W"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:20.029Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN034",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:25.125Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:29:08.581Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:29.320Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:54.202Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:20.029Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-08-09T16:35:12.943Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"034"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN034",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243104",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243104",
"modified": "2024-08-09T16:35:13.387Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_iRd8f2K---"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:03.587Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN036",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:33.027Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:31.618Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:18.754Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:03.587Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-05T20:41:20.182Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"036"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN036",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243106",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243106",
"modified": "2024-03-05T20:41:20.422Z",
"modifier": "arossel",
"rev": "_h6SHyk---N"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
},
{
"entContent": {
"approvedOn": "2023-08-11T16:07:10.417Z",
"description": "This version specified for the following genes: HNF1A",
"namespace": "GN017",
"releaseNotes": "Corrections to combining rules \n\nAdding previously omitted PVS1 Decision Tree and PS2 Points Table\n\nIndicated that gnomAD v.3.1.2 should be used for PM1\\_Supporting/BA1/BS1 frequency criteria for variants not covered in v2.1.1 exomes (consistent with recommendations of gnomAD based on sample sizes)",
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-08-11T16:07:10.417Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-02-05T03:53:36.999Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-25T19:15:04.115Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-11T15:50:52.587Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-25T18:50:17.656Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"017"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0",
"version": "2.1.0",
"versioned": true
},
"entId": "GN017",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "017_BP2_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "017",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903893",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903893",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpG--A"
},
{
"entContent": {
"_uniqueProp": "017_PP2_nuclear_HNF1A",
"additionalComments": "Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "017",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903884",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903884",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO---"
},
{
"entContent": {
"_uniqueProp": "017_PM4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "017",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For single amino acid deletions, use as supporting level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For single amino acid deletions/insertions, use as supporting level of evidence",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903880",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903880",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--I"
},
{
"entContent": {
"_uniqueProp": "017_BP7_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "017",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903897",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--H"
},
{
"entContent": {
"_uniqueProp": "017_BP4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "017",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903895",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--C"
},
{
"entContent": {
"_uniqueProp": "017_BS4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "017",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903891",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903891",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--M"
},
{
"entContent": {
"_uniqueProp": "017_PS4_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"label": "PS4",
"ns": "017",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 unrelated occurrences = Moderate. ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903876",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903876",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--B"
},
{
"entContent": {
"_uniqueProp": "017_PS2_nuclear_HNF1A",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Use SVI recommended point-based system with MDEP specifications for “Phenotype Consistency”.",
"label": "PS2",
"ns": "017",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903874",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903874",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--E"
},
{
"entContent": {
"_uniqueProp": "017_BS1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "017",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD 2.1.1\\* Popmax Filtering AF.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903888",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903888",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe---"
},
{
"entContent": {
"_uniqueProp": "017_PP4_nuclear_HNF1A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"label": "PP4",
"ns": "017",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:\n* Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis\n* Response to low-dose SU (extreme response- hypoglycemia)\n* Low hsCRP in patient with clinical diagnosis of T2DM\n* Biochemical/Molecular phenotypic evidence from patient cell lines\n* Hepatocellular adenomas",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903886",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903886",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--B"
},
{
"entContent": {
"_uniqueProp": "017_PP1_nuclear_HNF1A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"label": "PP1",
"ns": "017",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/32 (5 meioses) \n* >1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/16 (4 meioses)\n* >1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning (PMID: 27236918)\n* Single Family : ≤ 1/8 (3 meioses) \n* >1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903883",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903883",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--L"
},
{
"entContent": {
"_uniqueProp": "017_PM1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "017",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion can be used for variants in residues that directly bind DNA: Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273 ",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use for defined regions in the DNA binding and dimerization domains. \n* Dimerization: codons 1-32, NM_000545.8 \n* Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 \nIt can also be used for variants within certain transcription factor binding sites of the promoter. \n* –c.-187 to c.-195 (AP1 binding site) \n* –c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) \n* –c.-238 to c.-259 (HNF1A binding site) \n* –c.-276 to c.-288 (HNF4A binding site) \n ",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903877",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903877",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--A"
},
{
"entContent": {
"_uniqueProp": "017_PVS1_nuclear_HNF1A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Use HNF1A PVS1 decision tree.",
"label": "PVS1",
"ns": "017",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use HNF1A PVS1 decision tree.\n* Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.\n * PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.\n* Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.\n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903872",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903872",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--A"
},
{
"entContent": {
"_uniqueProp": "017_BP6_nuclear_HNF1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "017",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433450",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433450",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--L"
},
{
"entContent": {
"_uniqueProp": "017_BP5_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "017",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in other monogenic diabetes gene is P/LP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903896",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--D"
},
{
"entContent": {
"_uniqueProp": "017_BP3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "017",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903894",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903894",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--_"
},
{
"entContent": {
"_uniqueProp": "017_BP1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "017",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903892",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903892",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--G"
},
{
"entContent": {
"_uniqueProp": "017_BS3_nuclear_HNF1A",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "017",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. \n(1) Luciferase assays for transactivation - \"No functional impact\" is defined as ≥ 75% activity of wildtype\n(2) EMSA for DNA binding - \"No functional impact\" is defined as ≥ 75% activity of wildtype.\n(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903890",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903890",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--M"
},
{
"entContent": {
"_uniqueProp": "017_PP3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "017",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903885",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903885",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpi--D"
},
{
"entContent": {
"_uniqueProp": "017_PM3_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "017",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903879",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903879",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpG---"
},
{
"entContent": {
"_uniqueProp": "017_PM2_nuclear_HNF1A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2\\_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2\\_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2\\_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2\\_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1.",
"label": "PM2",
"ns": "017",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population. \n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903878",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903878",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpi--C"
},
{
"entContent": {
"_uniqueProp": "017_PP5_nuclear_HNF1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "017",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433451",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433451",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--J"
},
{
"entContent": {
"_uniqueProp": "017_BS2_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "017",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903889",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903889",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--C"
},
{
"entContent": {
"_uniqueProp": "017_BA1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "017",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD 2.1.1\\* Popmax Filtering AF.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903887",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903887",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--K"
},
{
"entContent": {
"_uniqueProp": "017_PM6_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "017",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903882",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903882",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--_"
},
{
"entContent": {
"_uniqueProp": "017_PM5_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "017",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903881",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903881",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--E"
},
{
"entContent": {
"_uniqueProp": "017_PS3_nuclear_HNF1A",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": "See list of approved functional studies and guidelines for interpretation of data.",
"label": "PS3",
"ns": "017",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 https://pubmed.ncbi.nlm.nih.gov/32910913/)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See list of approved functional studies and guidelines for interpretation of data (below).\n(1) Luciferase assays for transactivation - \"Decreased function\" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.\n(2) EMSA for DNA binding - \"Decreased function\" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.\n(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903875",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903875",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpO--D"
},
{
"entContent": {
"_uniqueProp": "017_PS1_nuclear_HNF1A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF1A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "017",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467903873",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467903873",
"modified": "2023-08-11T16:07:11.035Z",
"modifier": "tonipollin",
"rev": "_h6SHxpG--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1392102"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
"https://doi.org/10.2337/dci20-0065"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "monogenic diabetes",
"xrefs": [
"NCIT:C129739"
]
},
{
"pred": "hasExactSynonym",
"val": "rare genetic diabetes mellitus",
"xrefs": [
"Orphanet:183625"
]
}
],
"xrefs": [
{
"val": "EFO:1001511"
},
{
"val": "MEDGEN:1392102"
},
{
"val": "NCIT:C129739"
},
{
"val": "Orphanet:183625"
},
{
"val": "UMLS:C3888631"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://genboree.org/cspec/Disease/id/467884025",
"modified": "2025-10-07T15:45:43.374Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xjrq---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949436317700,
"agr": "HGNC:11621",
"alias_symbol": [
"HNF1",
"LFB1",
"HNF1α"
],
"ccds_id": [
"CCDS9209",
"CCDS76611"
],
"cosmic": "HNF1A",
"date_approved_reserved": "1990-02-12",
"date_modified": "2021-05-26",
"date_name_changed": "2007-08-24",
"date_symbol_changed": "2007-08-24",
"ena": [
"M57732"
],
"ensembl_gene_id": "ENSG00000135100",
"entrez_id": "6927",
"gene_group": [
"HNF class homeoboxes"
],
"gene_group_id": [
524
],
"hgnc_id": "HGNC:11621",
"homeodb": 8444,
"location": "12q24.31",
"location_sortable": "12q24.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/HNF1A",
"LRG_522|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_522.xml"
],
"mane_select": [
"ENST00000257555.11",
"NM_000545.8"
],
"mgd_id": [
"MGI:98504"
],
"name": "HNF1 homeobox A",
"omim_id": [
"142410"
],
"orphanet": 158583,
"prev_name": [
"transcription factor 1, hepatic; LF-B1, hepatic nuclear factor (HNF1), albumin proximal factor"
],
"prev_symbol": [
"MODY3",
"TCF1"
],
"pubmed_id": [
1535333,
7795649
],
"refseq_accession": [
"NM_000545"
],
"rgd_id": [
"RGD:3828"
],
"status": "Approved",
"symbol": "HNF1A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001tzg.4",
"uniprot_ids": [
"P20823"
],
"uuid": "a2a9a790-d0af-471d-889d-7588fb461df1",
"vega_id": "OTTHUMG00000151015"
}
},
"entId": "HNF1A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11621",
"entType": "Gene",
"ldhId": "467829599",
"ldhIri": "https://genboree.org/cspec/Gene/id/467829599",
"modified": "2021-10-14T11:36:42.130Z",
"modifier": "genbadmin",
"rev": "_h6SHz----A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "017_nuclear_HNF1A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0015967",
"preferredTitle": "monogenic diabetes"
}
],
"gene": "HNF1A",
"preferredTranscript": "NM_000545.8"
}
],
"ns": "017",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule13, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "467903870",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/467903870",
"modified": "2023-08-11T16:07:10.928Z",
"modifier": "tonipollin",
"rev": "_h6SHyTW-_-"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-11-21T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-06-04T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-08-18T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Monogenic Diabetes",
"shortBaseName": "Diabetes",
"shortTitle": "Monogenic Diabetes VCEP",
"title": "Monogenic Diabetes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50016",
"entIri": "http://clinicalgenome.org/affiliation/50016",
"entType": "Organization",
"ldhId": "135637640",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637640",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--I"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "467903868",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467903868",
"modified": "2023-09-29T15:16:48.007Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--J"
},
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "018_BS4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable as these are de novo, germline mosaic or post-zygotic mutations.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "018",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907180",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907180",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--A"
},
{
"entContent": {
"_uniqueProp": "018_BS2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "018",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.\nClinical laboratories are encouraged to accumulate more than 2 (≥3) instances of well phenotyped family members before applying this strong criterion. To be considered for this point, the variant should be either germline (most common), or somatic in a relevant tissue. Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907178",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907178",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpW--_"
},
{
"entContent": {
"_uniqueProp": "018_PS2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "018",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. \n\n Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.\n\n Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).\n\nFor the sake of implementation, these criteria are intended to apply to high-confidence somatic mutations identified by the reporting CLIA laboratory. The expert panel recognizes that in practice there may be significant heterogeneity in the technical methods and thresholds used to identify such variants as 'high confidence', and flags the need to establish consensus statistical frameworks (e.g. Phred-scaled genotype qualities) or experimental approaches (e.g., confirmation of somatic variants by sequencing on orthogonal platforms) by which quality thresholds can be consistently applied.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907163",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907163",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--_"
},
{
"entContent": {
"_uniqueProp": "018_PP4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since this criterion is accounted for under PS4.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "018",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907175",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907175",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--Q"
},
{
"entContent": {
"_uniqueProp": "018_PP3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "018",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0062",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907174",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907174",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--H"
},
{
"entContent": {
"_uniqueProp": "018_PM1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "018",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0054",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Residues affecting critical functional domains provided in Table 4 for each gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907166",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907166",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---G"
},
{
"entContent": {
"_uniqueProp": "018_PS4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "018",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0029",
"instructionsToUse": "",
"specificationType": "Disease-specific, Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4\\_VeryStrong ≥ 16 points. For PS4, for cases reported in the literature, we recommend assigning each one to the SINGLE category below that is associated with the highest point value (Table 2A). The total score obtained for all reported cases with a particular variant will determine the strength of PS4 assigned according to the scale (Table 2B)*.\n\n_PS4\\_VeryStrong ≥ 16 points._\n\n*Applicable if the variant is absent/rare from controls according to PM2 to ensure the variant is not simply present due to beinging common in the general population.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Strong = 3.5-15.75 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Moderate = 1.5-3.25 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907165",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907165",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxp---L"
},
{
"entContent": {
"_uniqueProp": "018_PVS1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF).",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "018",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0017",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907161",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907161",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--S"
},
{
"entContent": {
"_uniqueProp": "018_PS1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "018",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907162",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907162",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--N"
},
{
"entContent": {
"_uniqueProp": "018_PP5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "018",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433481",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433481",
"modified": "2022-01-19T20:31:34.845Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--N"
},
{
"entContent": {
"_uniqueProp": "018_BP7_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "018",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907186",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907186",
"modified": "2021-11-05T21:07:14.143Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--O"
},
{
"entContent": {
"_uniqueProp": "018_BP5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "018",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0078",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "No change.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907185",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907185",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq---"
},
{
"entContent": {
"_uniqueProp": "018_BP4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "018",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.\nNot applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907184",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907184",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpC--_"
},
{
"entContent": {
"_uniqueProp": "018_BP3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "018",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907183",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907183",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--I"
},
{
"entContent": {
"_uniqueProp": "018_BP2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "018",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis or trans with a known pathogenic variant in the same gene.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907182",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907182",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpC---"
},
{
"entContent": {
"_uniqueProp": "018_BP1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable as LOF is not the disease mechanism.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "018",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907181",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907181",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--V"
},
{
"entContent": {
"_uniqueProp": "018_BS3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "018",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907179",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907179",
"modified": "2022-01-19T20:33:35.979Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--U"
},
{
"entContent": {
"_uniqueProp": "018_BA1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "018",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.\n Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907176",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907176",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpO--B"
},
{
"entContent": {
"_uniqueProp": "018_PP2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "018",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907173",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907173",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--P"
},
{
"entContent": {
"_uniqueProp": "018_PP1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "018",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907172",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907172",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxpG--G"
},
{
"entContent": {
"_uniqueProp": "018_PM5_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "018",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907170",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907170",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--_"
},
{
"entContent": {
"_uniqueProp": "018_PM4_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "018",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "009",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907169",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907169",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--O"
},
{
"entContent": {
"_uniqueProp": "018_PM3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "Not applicable since disease-causing variants are heterozygous.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "018",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907168",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907168",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---I"
},
{
"entContent": {
"_uniqueProp": "018_PM2_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "018",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907167",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907167",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---H"
},
{
"entContent": {
"_uniqueProp": "018_PS3_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": "**Document 1. (PS3)**\n\n**Functional Assay Validation** \n\nPMID: 31892348\n\n1. The 4 classes of assays (phosphorylation, DEPTOR binding, cell survivability, cell proliferation) are considered “broadly accepted historically” for these genes. \n2. Any publication within the spreadsheet can be used as evidence for a supporting level of evidence (PS3).\n3. Any paper must have validation controls (positive and negative) in order to be used as evidence for a level above supporting. Positive validation controls are defined as variants classified as pathogenic/likely pathogenic (P/LP) independent of the PS3 criterion. Negative validation controls are defined as variants classified as benign/likely benign independent of the BS3 criterion\n * 8-34 variants are required for moderate evidence.\n * 35+ variants are required for strong evidence.\n4. For a publication to be used for any strength of evidence above supporting, it must also meet the minimum criteria below, depending on the type of evidence:\n\n**Supplemental Table 1**\n\n**Evidence from Phosphorylation/Deptor Binding/Cell Survivability Assay:**\n\n (Assay Controls) \n\n* Basic Positive Control – WT necessary \n* Basic Negative Control – Empty vector or blank transfection can be used. \n* Biological Replicates – not necessary \n* Technical Replicates – yes, documented in at least triplicate (You can contact the researcher and ask if it is not specifically mentioned in the publication.)\n\n**Evidence of Cell Proliferation:**\n\n* Basic Positive Control - WT necessary \n* Basic Negative Control – Empty vector or blank transfection can be used. \n* Biological Replicates – Necessary for animal studies (e.g., each mouse is a replicate, need at least 2) \n* Technical Replicates – Necessary, multiple samples measured from the same animal or experiment done in triplicate (at least 3)",
"label": "PS3",
"ns": "018",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. (Supplemental Document 1) Animal models are considered in a different manner.\n\nAward PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors shows a complementary brain phenotype.\n\nAward PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.\n\nAnimal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.\n\nCaveat: Studies of cell lines derived from the affected patient as the only source of functional characterization are by themselves insufficient to provide strong evidence of pathogenicity. This is because cells derived from patient affected tissue are likely to exhibit the desired phenotype since the patient tissue exhibits the phenotype. It is therefore impossible to determine whether the variant of interest was solely responsible for that phenotype. Instead, functional readout of patient-derived cells are now included in PS4.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907164",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907164",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxp---K"
},
{
"entContent": {
"_uniqueProp": "018_BP6_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "018",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433480",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433480",
"modified": "2022-01-19T20:31:34.845Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--M"
},
{
"entContent": {
"_uniqueProp": "018_BS1_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "018",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved. (Supplemental Table 3).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907177",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907177",
"modified": "2022-11-11T18:08:11.820Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpW---"
},
{
"entContent": {
"_uniqueProp": "018_PM6_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"additionalComments": "This point is addressed according to PS2 and will not be used.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"AKT3",
"MTOR",
"PIK3CA",
"PIK3R2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "018",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "467907171",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/467907171",
"modified": "2022-01-19T20:33:35.978Z",
"modifier": "genbadmin",
"rev": "_h6SHxom--T"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016054",
"lbl": "obsolete cerebral malformation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5114"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6876"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_cerebral_malformation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015219"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199633"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "brain malformation"
}
],
"xrefs": [
{
"val": "NANDO:2100217"
},
{
"val": "Orphanet:199633"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016054",
"name": "obsolete cerebral malformation"
},
"entId": "MONDO:0016054",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016054",
"entType": "Disease",
"ldhId": "467882125",
"ldhIri": "https://genboree.org/cspec/Disease/id/467882125",
"modified": "2025-10-07T15:45:45.208Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xlb2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056942263009300,
"agr": "HGNC:393",
"alias_name": [
"protein kinase B, gamma"
],
"alias_symbol": [
"PKBG",
"RAC-gamma",
"PRKBG"
],
"ccds_id": [
"CCDS31076",
"CCDS31077"
],
"date_approved_reserved": "1999-11-16",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-04",
"ena": [
"AF124141"
],
"ensembl_gene_id": "ENSG00000117020",
"entrez_id": "10000",
"enzyme_id": [
"2.7.11.1"
],
"gene_group": [
"Pleckstrin homology domain containing",
"AKT kinases"
],
"gene_group_id": [
682,
1900
],
"hgnc_id": "HGNC:393",
"iuphar": "objectId:2286",
"location": "1q43-q44",
"location_sortable": "01q43-q44",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1396|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1396.xml"
],
"mane_select": [
"ENST00000673466.1",
"NM_005465.7"
],
"mgd_id": [
"MGI:1345147"
],
"name": "AKT serine/threonine kinase 3",
"omim_id": [
"611223"
],
"orphanet": 299660,
"prev_name": [
"v-akt murine thymoma viral oncogene homolog 3"
],
"pubmed_id": [
10092583,
10208883
],
"refseq_accession": [
"NM_181690"
],
"rgd_id": [
"RGD:62390"
],
"status": "Approved",
"symbol": "AKT3",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc057qvr.1",
"uniprot_ids": [
"Q9Y243"
],
"uuid": "b261d7a3-a19d-49d9-9583-fa512693ef3b",
"vega_id": "OTTHUMG00000039994"
}
},
"entId": "AKT3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:393",
"entType": "Gene",
"ldhId": "467816839",
"ldhIri": "https://genboree.org/cspec/Gene/id/467816839",
"modified": "2021-10-14T11:36:28.929Z",
"modifier": "genbadmin",
"rev": "_h6SHyB2--E"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957530275800,
"agr": "HGNC:8980",
"alias_name": [
"phosphoinositide-3-kinase regulatory subunit beta"
],
"alias_symbol": [
"P85B",
"p85"
],
"ccds_id": [
"CCDS12371"
],
"date_approved_reserved": "1992-12-08",
"date_modified": "2021-04-13",
"date_name_changed": "2015-11-17",
"ensembl_gene_id": "ENSG00000105647",
"entrez_id": "5296",
"gene_group": [
"SH2 domain containing"
],
"gene_group_id": [
741
],
"hgnc_id": "HGNC:8980",
"iuphar": "objectId:2504",
"location": "19p13.11",
"location_sortable": "19p13.11",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1392|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1392.xml"
],
"mane_select": [
"ENST00000222254.13",
"NM_005027.4"
],
"mgd_id": [
"MGI:1098772"
],
"name": "phosphoinositide-3-kinase regulatory subunit 2",
"omim_id": [
"603157"
],
"orphanet": 306122,
"prev_name": [
"phosphoinositide-3-kinase, regulatory subunit 2 (beta)"
],
"pubmed_id": [
1314371
],
"refseq_accession": [
"NM_005027"
],
"rgd_id": [
"RGD:68341"
],
"status": "Approved",
"symbol": "PIK3R2",
"ucsc_id": "uc002nia.3",
"uniprot_ids": [
"O00459"
],
"uuid": "6beadeec-7569-46fa-a896-b395675058fc",
"vega_id": "OTTHUMG00000183383"
}
},
"entId": "PIK3R2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8980",
"entType": "Gene",
"ldhId": "467845253",
"ldhIri": "https://genboree.org/cspec/Gene/id/467845253",
"modified": "2021-10-14T11:36:58.187Z",
"modifier": "genbadmin",
"rev": "_h6SHzmC--S"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056957518741500,
"agr": "HGNC:8975",
"alias_symbol": [
"PI3K"
],
"ccds_id": [
"CCDS43171"
],
"cosmic": "PIK3CA",
"date_approved_reserved": "1994-07-15",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-17",
"ensembl_gene_id": "ENSG00000121879",
"entrez_id": "5290",
"enzyme_id": [
"2.7.1.153"
],
"gene_group": [
"Phosphatidylinositol 3-kinase subunits"
],
"gene_group_id": [
831
],
"hgnc_id": "HGNC:8975",
"iuphar": "objectId:2153",
"location": "3q26.32",
"location_sortable": "03q26.32",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_310|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_310.xml"
],
"mane_select": [
"ENST00000263967.4",
"NM_006218.4"
],
"mgd_id": [
"MGI:1206581"
],
"name": "phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha",
"omim_id": [
"171834"
],
"orphanet": 117820,
"prev_name": [
"phosphoinositide-3-kinase, catalytic, alpha polypeptide",
"phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha"
],
"pubmed_id": [
1322797
],
"refseq_accession": [
"NM_006218"
],
"rgd_id": [
"RGD:620916"
],
"status": "Approved",
"symbol": "PIK3CA",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003fjk.4",
"uniprot_ids": [
"P42336"
],
"uuid": "d302e43e-131c-425a-8243-83dfa167561a",
"vega_id": "OTTHUMG00000157311"
}
},
"entId": "PIK3CA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8975",
"entType": "Gene",
"ldhId": "467845243",
"ldhIri": "https://genboree.org/cspec/Gene/id/467845243",
"modified": "2021-10-14T11:36:58.187Z",
"modifier": "genbadmin",
"rev": "_h6SHznu--F"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056954987479000,
"agr": "HGNC:3942",
"alias_name": [
"FK506 binding protein 12-rapamycin associated protein 2",
"rapamycin target protein",
"FKBP12-rapamycin complex-associated protein 1",
"FKBP-rapamycin associated protein",
"rapamycin associated protein FRAP2",
"dJ576K7.1 (FK506 binding protein 12-rapamycin associated protein 1)",
"rapamycin and FKBP12 target 1",
"mammalian target of rapamycin"
],
"alias_symbol": [
"RAFT1",
"RAPT1",
"FLJ44809"
],
"ccds_id": [
"CCDS127"
],
"cosmic": "MTOR",
"date_approved_reserved": "1995-07-18",
"date_modified": "2021-05-26",
"date_name_changed": "2017-08-04",
"date_symbol_changed": "2009-05-29",
"ena": [
"L34075"
],
"ensembl_gene_id": "ENSG00000198793",
"entrez_id": "2475",
"gene_group": [
"MTOR complex 1",
"MTOR complex 2",
"Armadillo like helical domain containing"
],
"gene_group_id": [
1332,
1333,
1492
],
"hgnc_id": "HGNC:3942",
"iuphar": "objectId:2109",
"location": "1p36.22",
"location_sortable": "01p36.22",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_734|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_734.xml"
],
"mane_select": [
"ENST00000361445.9",
"NM_004958.4"
],
"mgd_id": [
"MGI:1928394"
],
"name": "mechanistic target of rapamycin kinase",
"omim_id": [
"601231"
],
"orphanet": 431220,
"prev_name": [
"FK506 binding protein 12-rapamycin associated protein 1",
"mechanistic target of rapamycin (serine/threonine kinase)",
"mechanistic target of rapamycin"
],
"prev_symbol": [
"FRAP",
"FRAP2",
"FRAP1"
],
"pubmed_id": [
8008069,
8660990
],
"refseq_accession": [
"NM_004958"
],
"rgd_id": [
"RGD:68371"
],
"status": "Approved",
"symbol": "MTOR",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001asd.4",
"uniprot_ids": [
"P42345"
],
"uuid": "793d0551-866d-4b38-9f14-6483dee31064",
"vega_id": "OTTHUMG00000002001"
}
},
"entId": "MTOR",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3942",
"entType": "Gene",
"ldhId": "467840946",
"ldhIri": "https://genboree.org/cspec/Gene/id/467840946",
"modified": "2021-10-14T11:36:54.131Z",
"modifier": "genbadmin",
"rev": "_h6SHzpG--N"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "018_nuclear_AKT3_MTOR_PIK3CA_PIK3R2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "AKT3",
"preferredTranscript": "NM_005465.4"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "MTOR",
"preferredTranscript": "NM_004958.3"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "PIK3CA",
"preferredTranscript": "NM_006218.3"
},
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "PIK3R2",
"preferredTranscript": "NM_005027.3"
}
],
"ns": "018",
"references": []
},
"entType": "RuleSet",
"ldhId": "467907154",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/467907154",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--I"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN064",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:25.817Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"064"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R2 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN064",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243134",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243134",
"modified": "2022-11-11T18:08:12.421Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--B"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN062",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:18.044Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"062"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTOR Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN062",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243132",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243132",
"modified": "2022-11-11T18:08:12.113Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--E"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN061",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:13.987Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"061"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for AKT3 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN061",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243131",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243131",
"modified": "2022-11-11T18:08:11.946Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--B"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN063",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:21.885Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"063"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CA Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN063",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243133",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243133",
"modified": "2022-11-11T18:08:12.252Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--C"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-10-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-05-14T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Brain Malformations",
"shortBaseName": "BrainMalform",
"shortTitle": "Brain Malformations VCEP",
"title": "Brain Malformations Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50020",
"entIri": "http://clinicalgenome.org/affiliation/50020",
"entType": "Organization",
"ldhId": "135637641",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637641",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
},
{
"entContent": {
"approvedOn": "2021-11-19T00:00:00.000Z",
"description": "This version specified for the following genes: MYOC",
"namespace": "GN019",
"releaseNotes": "Added MYOC HGNC ID, Replaced disease identifiers Primary open-angle glaucoma (POAG) and juvenile onset open-angle glaucoma (JOAG) (MIM: 137750) with primary open angle glaucoma (MONDO:0007665) and juvenile open angle glaucoma (MONDO:0020367).",
"shortTitle": "Glaucoma",
"specificationSource": "https://clinicalgenome.org/docs/clingen-glaucoma-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"019"
],
"title": "ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1",
"version": "1.1.0"
},
"entId": "GN019",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "019_BP3_nuclear_MYOC",
"additionalComments": "MYOC does not have a repetitive region without a known function.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "019",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003705",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003705",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK--_"
},
{
"entContent": {
"_uniqueProp": "019_PM6_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "019",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥2 assumed de novo in JOAG.\nUse proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥2 assumed de novo in POAG or 1 assumed de novo in JOAG\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003693",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003693",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--C"
},
{
"entContent": {
"_uniqueProp": "019_PS2_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "019",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 confirmed de novo in JOAG.\nUse the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.\n * Both maternity and paternity need to be proven for confirmed de novo variants.\n * Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 confirmed de novo in POAG.\nUse proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG. \n * Both maternity and paternity need to be proven for confirmed de novo variants. \n * Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003685",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003685",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--G"
},
{
"entContent": {
"_uniqueProp": "019_BP7_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "019",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003708",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003708",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--C"
},
{
"entContent": {
"_uniqueProp": "019_BP4_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "019",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applies to:\n * Missense variants with a REVEL score of ≤ 0.15.\n * Synonymous variants or noncoding variants with a CADD score of ≤ 10 AND SpliceAI ≤ 0.2",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003706",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003706",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--D"
},
{
"entContent": {
"_uniqueProp": "019_BS3_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "019",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.\n* Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.\n* Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n* If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n* Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n* If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003701",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003701",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--K"
},
{
"entContent": {
"_uniqueProp": "019_BS1_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "019",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency ≥ 0.001 in population databases.\n * The highest allele frequency in population databases should be used. \n * Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. \n * Does not apply to p.Gln368Ter.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003699",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003699",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoi--I"
},
{
"entContent": {
"_uniqueProp": "019_PP4_nuclear_MYOC",
"additionalComments": "The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "019",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003697",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003697",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--_"
},
{
"entContent": {
"_uniqueProp": "019_BP6_nuclear_MYOC",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYOC"
],
"instructionsToUse": "",
"label": "BP6",
"ns": "019",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433510",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433510",
"modified": "2022-01-19T20:31:35.088Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--F"
},
{
"entContent": {
"_uniqueProp": "019_BP2_nuclear_MYOC",
"additionalComments": "Biallelic variants (either compound heterozygotes or homozygotes) have been reported (with variable phenotype) and are not incompatible with life. Two missense variants in cis could act synergistically or the effect of a variant occurring after a truncating variant may not be predicted.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "019",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003704",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003704",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--D"
},
{
"entContent": {
"_uniqueProp": "019_PM5_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "019",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)\n * The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same residue as a previously established likely pathogenic variant (assessed independently of PM5).\n * The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003692",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003692",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--J"
},
{
"entContent": {
"_uniqueProp": "019_PM1_nuclear_MYOC",
"additionalComments": "MYOC has no mutational hot spot and benign variants are present though the well-characterised olfactomedin domain in exon 3.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "019",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003688",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003688",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK---"
},
{
"entContent": {
"_uniqueProp": "019_PP5_nuclear_MYOC",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYOC"
],
"instructionsToUse": "",
"label": "PP5",
"ns": "019",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "638433511",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/638433511",
"modified": "2022-01-19T20:31:35.088Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6---"
},
{
"entContent": {
"_uniqueProp": "019_BP5_nuclear_MYOC",
"additionalComments": "Multiple molecular diagnoses are possible and variants in different genes could have an additive effect.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "019",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003707",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003707",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK--A"
},
{
"entContent": {
"_uniqueProp": "019_BS2_nuclear_MYOC",
"additionalComments": "MYOC variants have an incomplete penetrance and late age of onset.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "019",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003700",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003700",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--C"
},
{
"entContent": {
"_uniqueProp": "019_PP3_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "019",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Applies to missense variants with a REVEL score of ≥ 0.7.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003696",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003696",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--M"
},
{
"entContent": {
"_uniqueProp": "019_PP2_nuclear_MYOC",
"additionalComments": "Although pathogenic missense variants are common in MYOC, the gene also has a significant amount of benign missense variants as shown by the missense constraint z score in gnomAD (z = 0.52) supporting tolerance to variation.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "019",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003695",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003695",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--R"
},
{
"entContent": {
"_uniqueProp": "019_PP1_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "019",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 meioses in >1 family.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥ 5 meioses.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥ 3 meioses.\n * BA1 and BS1 must not be met.\n * Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.\n * Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003694",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003694",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--A"
},
{
"entContent": {
"_uniqueProp": "019_PM4_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "019",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003691",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003691",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--I"
},
{
"entContent": {
"_uniqueProp": "019_PM3_nuclear_MYOC",
"additionalComments": "MYOC variants have an autosomal dominant mode of inheritance.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "019",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003690",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003690",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxp---J"
},
{
"entContent": {
"_uniqueProp": "019_PS4_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "019",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥ 15 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥ 6 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥ 2 probands from multiple independent studies.\n * Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.\n * PM2_Supporting must be met.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003687",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003687",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--H"
},
{
"entContent": {
"_uniqueProp": "019_PS1_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "019",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* The novel change must not affect splicing (SpliceAI ≤ 0.2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established likely pathogenic variant\n * The novel change must not affect splicing (SpliceAI ≤ 0.2).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003684",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003684",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--K"
},
{
"entContent": {
"_uniqueProp": "019_PVS1_nuclear_MYOC",
"additionalComments": "MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "019",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0017",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003683",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003683",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--B"
},
{
"entContent": {
"_uniqueProp": "019_BP1_nuclear_MYOC",
"additionalComments": "Both truncating and missense MYOC variants are causative.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "019",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003703",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003703",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--A"
},
{
"entContent": {
"_uniqueProp": "019_BS4_nuclear_MYOC",
"additionalComments": "The presence of phenocopies, the reduced age-related penetrance and the possibility that more than one pathogenic variant can contribute to the phenotype observed in families make non-segregation difficult to assess in the context of MYOC and POAG.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "019",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003702",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003702",
"modified": "2022-01-19T20:33:36.129Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--S"
},
{
"entContent": {
"_uniqueProp": "019_BA1_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "019",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency ≥ 0.01 in population databases.\n * The highest allele frequency in population databases should be used.\n * Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003698",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003698",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--B"
},
{
"entContent": {
"_uniqueProp": "019_PM2_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "019",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Allele frequency ≤ 0.0001 in population databases.\n * The highest allele frequency in population databases should be used. \n * Only applies to populations of ≥ 10,000 alleles.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003689",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003689",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoe--B"
},
{
"entContent": {
"_uniqueProp": "019_PS3_nuclear_MYOC",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYOC"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "019",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assays with OddsPath >18.7 as per the SVI recommendations.\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assays with OddsPath >4.3 as per the SVI recommendations\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assays with OddsPath >2.1 as per the SVI recommendations.\n * Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.\n * PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.\n * If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.\n * Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.\n * If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "635003686",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/635003686",
"modified": "2021-12-03T23:10:37.640Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--L"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007665",
"lbl": "obsolete glaucoma 1, open angle, E",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/2507"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4936"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0100001",
"val": "http://purl.obolibrary.org/obo/MONDO_0100553"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/glaucoma_primary_open_angle"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C562750"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/77075001"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1070"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C35394"
}
],
"definition": {
"val": "OBSOLETE. A form of glaucoma in which there is no visible abnormality in the trabecular meshwork.",
"xrefs": [
"NCIT:C35394"
]
},
"deprecated": true,
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "chronic simple glaucoma"
}
],
"xrefs": [
{
"val": "DOID:1070"
},
{
"val": "ICD9:365.11"
},
{
"val": "MESH:C562750"
},
{
"val": "NCIT:C35394"
},
{
"val": "SCTID:77075001"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007665",
"name": "obsolete glaucoma 1, open angle, E"
},
"entId": "MONDO:0007665",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007665",
"entType": "Disease",
"ldhId": "467890796",
"ldhIri": "https://genboree.org/cspec/Disease/id/467890796",
"modified": "2025-10-07T15:43:30.403Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vh0e---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0020367",
"lbl": "juvenile open angle glaucoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6877"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/juvenile_glaucoma"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10064032"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/453382"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/71111008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2981140"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1068"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_98977"
}
],
"definition": {
"val": "Juvenile glaucoma (JG) is a rare autosomal dominant open angle glaucoma, characterized by early onset, severe elevation of intra ocular pressure of rapid progression, leading to optic nerve excavation and, when untreated, substantial visual impairment.",
"xrefs": [
"Orphanet:98977"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "JOAG"
},
{
"pred": "hasExactSynonym",
"val": "childhood glaucoma (disease)"
},
{
"pred": "hasExactSynonym",
"val": "glaucoma (disease) of childhood",
"xrefs": [
"MONDO:patterns/childhood"
]
},
{
"pred": "hasExactSynonym",
"val": "glaucoma of childhood",
"xrefs": [
"DOID:1068",
"ICD9CM:365.14"
]
},
{
"pred": "hasExactSynonym",
"val": "juvenile glaucoma",
"xrefs": [
"DOID:1068",
"Orphanet:98977"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "paediatric glaucoma (disease)"
},
{
"pred": "hasExactSynonym",
"val": "pediatric glaucoma (disease)",
"xrefs": [
"MONDO:patterns/childhood"
]
}
],
"xrefs": [
{
"val": "DOID:1068"
},
{
"val": "GARD:16883"
},
{
"val": "ICD9:365.14"
},
{
"val": "MEDGEN:453382"
},
{
"val": "MedDRA:10064032"
},
{
"val": "Orphanet:98977"
},
{
"val": "SCTID:71111008"
},
{
"val": "UMLS:C2981140"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0020367",
"name": "juvenile open angle glaucoma"
},
"entId": "MONDO:0020367",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0020367",
"entType": "Disease",
"ldhId": "467891695",
"ldhIri": "https://genboree.org/cspec/Disease/id/467891695",
"modified": "2025-10-07T15:47:00.768Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YvUG---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955127988200,
"agr": "HGNC:7610",
"alias_name": [
"trabecular meshwork inducible glucocorticoid response protein",
"juvenile-onset open-angle glaucoma 1"
],
"alias_symbol": [
"TIGR",
"JOAG1"
],
"ccds_id": [
"CCDS1297"
],
"date_approved_reserved": "1997-01-10",
"date_modified": "2016-10-05",
"date_name_changed": "2016-03-08",
"ena": [
"BC029261"
],
"ensembl_gene_id": "ENSG00000034971",
"entrez_id": "4653",
"hgnc_id": "HGNC:7610",
"location": "1q24.3",
"location_sortable": "01q24.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000037502.11",
"NM_000261.2"
],
"mgd_id": [
"MGI:1202864"
],
"name": "myocilin",
"omim_id": [
"601652"
],
"orphanet": 123659,
"prev_name": [
"myocilin, trabecular meshwork inducible glucocorticoid response"
],
"prev_symbol": [
"GLC1A"
],
"pubmed_id": [
9169133,
9005853
],
"refseq_accession": [
"NM_000261"
],
"rgd_id": [
"RGD:620430"
],
"status": "Approved",
"symbol": "MYOC",
"ucsc_id": "uc001ghu.4",
"uniprot_ids": [
"Q99972"
],
"uuid": "cf4e7806-a21a-4e2e-8df8-5bb6a816da8a",
"vega_id": "OTTHUMG00000034789"
}
},
"entId": "MYOC",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7610",
"entType": "Gene",
"ldhId": "467841186",
"ldhIri": "https://genboree.org/cspec/Gene/id/467841186",
"modified": "2021-10-14T11:36:54.363Z",
"modifier": "genbadmin",
"rev": "_h6SHznW--D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "019_nuclear_MYOC",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0007665",
"preferredTitle": "primary open angle glaucoma"
},
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0020367",
"preferredTitle": "juvenile open angle glaucoma"
}
],
"gene": "MYOC",
"preferredTranscript": "NM_000261.1"
}
],
"ns": "019",
"references": []
},
"entType": "RuleSet",
"ldhId": "635003681",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/635003681",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--R"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2019-08-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-03-02T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-09-16T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-10-27T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Glaucoma",
"shortBaseName": "Glaucoma",
"shortTitle": "Glaucoma VCEP",
"title": "Glaucoma Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50053",
"entIri": "https://clinicalgenome.org/affiliation/50053",
"entType": "Organization",
"ldhId": "635003639",
"ldhIri": "https://genboree.org/cspec/Organization/id/635003639",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEC--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "635003679",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/635003679",
"modified": "2023-09-29T15:16:48.273Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--N"
},
{
"entContent": {
"approvedOn": "2023-11-28T19:21:26.653Z",
"description": "ACMG-modified rules specifications for ATM (autosomal dominant and autosomal recessive disorders)",
"namespace": "GN020",
"releaseNotes": "Release notes v1.2 \n• Updated verbiage from PVS1\\_O\\_Strength and BP7\\_O\\_Strength - Update: PVS1\\_Strength(RNA) and BP7\\_Strength(RNA) \n• Updated verbiage to clarify: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). \n• Update verbiage to clarify : Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2\\_supporting would not apply \n• Add same verbiage as PALB2 rules: Apply to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1\\_VS\\[RNA\\] is applied based on high quality observed splicing impact and must be NMD prone \n• Update typo: Update to: Do not use: ATM does not have a defined low rate of missense benign variation \n• Clarify in silico predictor verbiage (PP3/BP4 RNA details) \n• Update 1 VS + 1 supporting (not just PM2\\_supporting) reaches likely pathogenic \n• Updated PS1 tables to splicing group SVI tables \n• Added the supplementary tables from original rules that did not transfer into the CSPEC editor.",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP)",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-28T19:21:26.653Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-02-21T21:54:17.271Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-04T19:42:40.170Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-18T17:20:00.954Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-28T19:17:31.236Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-03-04T19:34:25.031Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"020"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.2.0",
"version": "1.2.0",
"versioned": true
},
"entId": "GN020",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "020_BP6_nuclear_ATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "020",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509017",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509017",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--D"
},
{
"entContent": {
"_uniqueProp": "020_PM5_nuclear_ATM",
"additionalComments": "No rescue splicing isoforms have been identified in ATM.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants",
"label": "PM5",
"ns": "020",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509000",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509000",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--U"
},
{
"entContent": {
"_uniqueProp": "020_PM1_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "020",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508996",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508996",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--3"
},
{
"entContent": {
"_uniqueProp": "020_PS2_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "020",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508993",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508993",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpa--L"
},
{
"entContent": {
"_uniqueProp": "020_PS1_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use as ascribed for protein changes as long as a splice defect is ruled out for both variants; Use Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205)",
"label": "PS1",
"ns": "020",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508992",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508992",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--4"
},
{
"entContent": {
"_uniqueProp": "020_BP5_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "020",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509016",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509016",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG---"
},
{
"entContent": {
"_uniqueProp": "020_PP3_nuclear_ATM",
"additionalComments": "Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Protein: REVEL >.7333\n\nRNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n\n* NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n* NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1\\_Variable(RNA) codes.\n* Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",
"label": "PP3",
"ns": "020",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509004",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509004",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--E"
},
{
"entContent": {
"_uniqueProp": "020_PP2_nuclear_ATM",
"additionalComments": "Do not use: ATM does not have a defined low rate of missense benign variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "020",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509003",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509003",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--_"
},
{
"entContent": {
"_uniqueProp": "020_PM3_nuclear_ATM",
"additionalComments": "Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PM3/BP2 table.",
"label": "PM3",
"ns": "020",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use ATM PM3/BP2 table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use ATM PM3/BP2 table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ATM PM3/BP2 table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ATM PM3/BP2 table",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508998",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508998",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--E"
},
{
"entContent": {
"_uniqueProp": "020_PM2_nuclear_ATM",
"additionalComments": "PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2\\_supporting would not apply",
"label": "PM2",
"ns": "020",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2\\_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2\\_supporting would not apply",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508997",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508997",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpa--M"
},
{
"entContent": {
"_uniqueProp": "020_PVS1_nuclear_ATM",
"additionalComments": "Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PVS1 Decision Tree.",
"label": "PVS1",
"ns": "020",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use ATM PVS1 Decision Tree",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use ATM PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use ATM PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use ATM PVS1 Decision Tree",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508991",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508991",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--A"
},
{
"entContent": {
"_uniqueProp": "020_BP3_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "020",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509014",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509014",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpa--O"
},
{
"entContent": {
"_uniqueProp": "020_BP2_nuclear_ATM",
"additionalComments": "Multiple such cases are additive, age considerations (>18yo) are required. Observations in cis are not applicable. Source information is considered (laboratory vs database setting).",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PM3/BP2 table.",
"label": "BP2",
"ns": "020",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use ATM PM3/BP2 table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Use ATM PM3/BP2 table.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use ATM PM3/BP2 table",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509013",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509013",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--V"
},
{
"entContent": {
"_uniqueProp": "020_BA1_nuclear_ATM",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Filtering Allele Frequency >.5%.",
"label": "BA1",
"ns": "020",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filtering Allele Frequency >.5%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509007",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509007",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--W"
},
{
"entContent": {
"_uniqueProp": "020_PP4_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "020",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509005",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509005",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--D"
},
{
"entContent": {
"_uniqueProp": "020_PM6_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "020",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509001",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509001",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--C"
},
{
"entContent": {
"_uniqueProp": "020_PS4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use for 'proband counting' method. Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).",
"label": "PS4",
"ns": "020",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Do not use for proband counting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508995",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508995",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpa--N"
},
{
"entContent": {
"_uniqueProp": "020_BP7_nuclear_ATM",
"additionalComments": "BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Use as BP7\\_(RNA) for synonymous and intronic variants with no splice defect observed. Weight for BP7\\_(RNA) is variable based on curator impression fo assay quality (not specified).",
"label": "BP7",
"ns": "020",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": "General recommendation",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Can be considered for BP7\\_(RNA) with curator discretion of quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Can be considered for BP7\\_(RNA) with curator discretion of quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Can be considered for BP7\\_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509018",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509018",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe---"
},
{
"entContent": {
"_uniqueProp": "020_BS1_nuclear_ATM",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Filtering Allele Frequency >.05%.",
"label": "BS1",
"ns": "020",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filtering Allele Frequency >.05%.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509008",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509008",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--H"
},
{
"entContent": {
"_uniqueProp": "020_PM4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.",
"label": "PM4",
"ns": "020",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use for stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508999",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508999",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--S"
},
{
"entContent": {
"_uniqueProp": "020_BP4_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "Protein: REVEL <.249; RNA: multiple in silico predictors agree to a lack of splice defect.",
"label": "BP4",
"ns": "020",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* **Protein** Analysis: Metapredictor REVEL score ≤.249\n* RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing \n * NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n * NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509015",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509015",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--J"
},
{
"entContent": {
"_uniqueProp": "020_BP1_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "020",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509012",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509012",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--Y"
},
{
"entContent": {
"_uniqueProp": "020_BS4_nuclear_ATM",
"additionalComments": "AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)\n. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "020",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509011",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509011",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpa--K"
},
{
"entContent": {
"_uniqueProp": "020_BS3_nuclear_ATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7\\_RNA and modulate strength based on assay quality and quantity (curator discretion).",
"label": "BS3",
"ns": "020",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509010",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509010",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--I"
},
{
"entContent": {
"_uniqueProp": "020_BS2_nuclear_ATM",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "020",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509009",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509009",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--R"
},
{
"entContent": {
"_uniqueProp": "020_PP5_nuclear_ATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "020",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509006",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509006",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--T"
},
{
"entContent": {
"_uniqueProp": "020_PP1_nuclear_ATM",
"additionalComments": "Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "020",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509002",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509002",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--G"
},
{
"entContent": {
"_uniqueProp": "020_PS3_nuclear_ATM",
"additionalComments": "Conflicting functional studies should not be given any weight.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ATM"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1\\_Strength(RNA) and modulate strength based on assay quality and quantity (curator discretion).",
"label": "PS3",
"ns": "020",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Do not use as strong.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639508994",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639508994",
"modified": "2023-11-28T19:21:27.379Z",
"modifier": "meganholdren",
"rev": "_h6SHxpC--X"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016419",
"lbl": "hereditary breast carcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016419"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hereditary_breast_carcinoma"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/87542"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C562840"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/254843006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0346153"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C4503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_227535"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/114480"
}
],
"comments": [
"Editor note: check w clingen before merge https://github.com/monarch-initiative/mondo/issues/84"
],
"definition": {
"val": "Breast carcinoma that has developed in relatives of patients with history of breast carcinoma.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "breast cancer susceptibility, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, early-onset, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, invasive ductal, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, lobular, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, male, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, protection against, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "familial breast cancer",
"xrefs": [
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial breast carcinoma",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of the breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast cancer",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast carcinoma",
"xrefs": [
"MONDO:patterns/hereditary",
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial"
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial Male"
}
],
"xrefs": [
{
"val": "GARD:17142"
},
{
"val": "ICD10CM:C50.2"
},
{
"val": "ICD10CM:C50.3"
},
{
"val": "ICD10CM:C50.6"
},
{
"val": "MEDGEN:87542"
},
{
"val": "MESH:C562840"
},
{
"val": "NCIT:C4503"
},
{
"val": "OMIM:114480"
},
{
"val": "Orphanet:227535"
},
{
"val": "SCTID:254843006"
},
{
"val": "UMLS:C0346153"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016419",
"name": "hereditary breast carcinoma"
},
"entId": "MONDO:0016419",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016419",
"entType": "Disease",
"ldhId": "467880845",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880845",
"modified": "2025-10-07T15:45:51.651Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XrmW---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018266",
"lbl": "ataxia - telangiectasia variant",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6877"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/406286"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1876175"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_370109"
}
],
"definition": {
"val": "Ataxia-telangiectasia variant is a rare, genetic, persistent combined dystonia characterized by clinical signs similar to ataxia-telangiectasia but with a later (usually adulthood) onset and slower progression. Patients typically present extrapyramidal signs, such as resting tremor, choreathetosis, and dystonia, as the initial symptoms and later often develop mild cerebellar ataxia (with gait usually preserved). Telangiectasia and immunodeficiency may be absent but secondary features of ataxia-telangiectasia, such as risk of malignancy, dysarthria and peripheral neuropathy, are frequently present.",
"xrefs": [
"Orphanet:370109"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "v-AT",
"xrefs": [
"Orphanet:370109"
]
}
],
"xrefs": [
{
"val": "GARD:21597"
},
{
"val": "MEDGEN:406286"
},
{
"val": "Orphanet:370109"
},
{
"val": "UMLS:C1876175"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018266",
"name": "ataxia - telangiectasia variant"
},
"entId": "MONDO:0018266",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018266",
"entType": "Disease",
"ldhId": "467877093",
"ldhIri": "https://genboree.org/cspec/Disease/id/467877093",
"modified": "2025-10-07T15:46:23.439Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YKzq---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0008840",
"lbl": "ataxia telangiectasia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5682"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8301"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0008840"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/ataxia_telangiectasia_2"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019293"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0042983"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/5862/ataxia-telangiectasia"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10003594"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/439"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D001260"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/68504005"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0004135"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12704"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C2887"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_100"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/208900"
}
],
"definition": {
"val": "Ataxia-telangiectasia is the association of severe combined immunodeficiency (affecting mainly the humoral immune response) with progressive cerebellar ataxia. It is characterized by neurological signs, telangiectasias, increased susceptibility to infections and a higher risk of cancer.",
"xrefs": [
"Orphanet:100"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Louis Bar syndrome",
"xrefs": [
"DOID:12704"
]
},
{
"pred": "hasExactSynonym",
"val": "Louis-Bar syndrome",
"xrefs": [
"NCIT:C2887",
"OMIM:208900",
"Orphanet:100"
]
},
{
"pred": "hasExactSynonym",
"val": "ataxia - telangiectasia",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasExactSynonym",
"val": "ataxia telangiectasia",
"xrefs": [
"DOID:12704",
"NCIT:C2887"
]
},
{
"pred": "hasExactSynonym",
"val": "ataxia telangiectasia syndrome",
"xrefs": [
"NCIT:C2887"
]
},
{
"pred": "hasExactSynonym",
"val": "boder-Sedgwick syndrome",
"xrefs": [
"DOID:12704"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "AT",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "AT, complementation group A"
},
{
"pred": "hasRelatedSynonym",
"val": "AT, complementation group C"
},
{
"pred": "hasRelatedSynonym",
"val": "AT, complementation group D"
},
{
"pred": "hasRelatedSynonym",
"val": "AT, complementation group E"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "AT1"
},
{
"pred": "hasRelatedSynonym",
"val": "ataxia - telangiectasia variant"
},
{
"pred": "hasRelatedSynonym",
"val": "ataxia-telangiectasia"
},
{
"pred": "hasRelatedSynonym",
"val": "cerebello-oculocutaneous telangiectasia",
"xrefs": [
"GARD:0005862"
]
},
{
"pred": "hasRelatedSynonym",
"val": "immunodeficiency with ataxia telangiectasia",
"xrefs": [
"GARD:0005862"
]
}
],
"xrefs": [
{
"val": "DOID:12704"
},
{
"val": "GARD:5862"
},
{
"val": "ICD9:334.8"
},
{
"val": "MEDGEN:439"
},
{
"val": "MESH:D001260"
},
{
"val": "MedDRA:10003594"
},
{
"val": "NANDO:1200331"
},
{
"val": "NANDO:2200705"
},
{
"val": "NCIT:C2887"
},
{
"val": "NORD:816"
},
{
"val": "OMIM:208900"
},
{
"val": "Orphanet:100"
},
{
"val": "SCTID:68504005"
},
{
"val": "UMLS:C0004135"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0008840",
"name": "ataxia telangiectasia"
},
"entId": "MONDO:0008840",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0008840",
"entType": "Disease",
"ldhId": "467877731",
"ldhIri": "https://genboree.org/cspec/Disease/id/467877731",
"modified": "2025-10-07T15:43:47.494Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vyay---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056942898446300,
"agr": "HGNC:795",
"alias_name": [
"TEL1, telomere maintenance 1, homolog (S. cerevisiae)"
],
"alias_symbol": [
"TEL1",
"TELO1"
],
"ccds_id": [
"CCDS86245",
"CCDS31669"
],
"cosmic": "ATM",
"date_approved_reserved": "1995-07-07",
"date_modified": "2021-04-13",
"date_name_changed": "2014-06-17",
"ena": [
"AB209133"
],
"ensembl_gene_id": "ENSG00000149311",
"entrez_id": "472",
"gene_group": [
"Armadillo like helical domain containing"
],
"gene_group_id": [
1492
],
"hgnc_id": "HGNC:795",
"iuphar": "objectId:1934",
"location": "11q22.3",
"location_sortable": "11q22.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Ataxia Telangiectasia Mutated (ATM)|http://www.LOVD.nl/ATM",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/ATM",
"LRG_135|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_135.xml"
],
"mane_select": [
"ENST00000675843.1",
"NM_000051.4"
],
"mgd_id": [
"MGI:107202"
],
"name": "ATM serine/threonine kinase",
"omim_id": [
"607585"
],
"orphanet": 121474,
"prev_name": [
"ataxia telangiectasia mutated (includes complementation groups A, C and D)",
"ataxia telangiectasia mutated"
],
"prev_symbol": [
"ATA",
"ATDC",
"ATC",
"ATD"
],
"refseq_accession": [
"NM_000051"
],
"rgd_id": [
"RGD:1593265"
],
"status": "Approved",
"symbol": "ATM",
"ucsc_id": "uc001pkb.1",
"uniprot_ids": [
"Q13315"
],
"uuid": "fdae88ce-f9d1-4acb-9bf9-0f13ff5bb57f",
"vega_id": "OTTHUMG00000166480"
}
},
"entId": "ATM",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:795",
"entType": "Gene",
"ldhId": "467818057",
"ldhIri": "https://genboree.org/cspec/Gene/id/467818057",
"modified": "2021-10-14T11:36:30.205Z",
"modifier": "genbadmin",
"rev": "_h6SHyD---Q"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "020_nuclear_ATM",
"geneType": "nuclear",
"generalComments": "Release notes v1.2 \n•\tUpdated verbiage from PVS1_O_Strength and BP7_O_Strength - Update: PVS1_Strength(RNA) and BP7_Strength(RNA)\n•\tUpdated verbiage to clarify: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).\n•\tUpdate verbiage to clarify : Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply\n•\tAdd same verbiage as PALB2 rules: Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS[RNA] is applied based on high quality observed splicing impact and must be NMD prone\n•\tUpdate typo: Update to: Do not use: ATM does not have a defined low rate of missense benign variation\n•\tClarify in silico predictor verbiage (PP3/BP4 RNA details) \n•\tUpdate 1 VS + 1 supporting (not just PM2_supporting) reaches likely pathogenic \n•\tUpdated PS1 tables to splicing group SVI tables \n•\tAdded the supplementary tables from original rules that did not transfer into the CSPEC editor. \n\n\n ",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": " Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0016419",
"preferredTitle": "hereditary breast carcinoma"
},
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0008840",
"preferredTitle": "ataxia telangiectasia"
},
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0018266",
"preferredTitle": "ataxia - telangiectasia variant"
}
],
"gene": "ATM",
"preferredTranscript": "NM_000051.3"
}
],
"ns": "020",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BP2_Strong",
"BP7_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BP2_Strong",
"BP7_Strong"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP3"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BP2_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule20"
}
]
}
},
"entType": "RuleSet",
"ldhId": "639508987",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/639508987",
"modified": "2023-11-28T19:21:27.286Z",
"modifier": "meganholdren",
"rev": "_h6SHyTW-_S"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "HBOP",
"approval": {
"step1": {
"approvalDate": "2018-11-28T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-10-31T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-01-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-01-25T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hereditary Breast, Ovarian and Pancreatic Cancer",
"shortBaseName": "HBOP",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer VCEP",
"title": "Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50039",
"entIri": "http://clinicalgenome.org/affiliation/50039",
"entType": "Organization",
"ldhId": "639508880",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508880",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--T"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "639508985",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639508985",
"modified": "2024-03-04T19:42:40.436Z",
"modifier": "meganholdren",
"rev": "_h6SHykG--f"
},
{
"entContent": {
"approvedOn": "2026-04-24T10:56:23.076Z",
"description": "ACADVL Specifications version 1.1 Test\n ",
"namespace": "GN021",
"releaseNotes": "* Test\n* Test 1\n* Demo ECT",
"shortTitle": "ACADVL Variant Curation Expert Panel",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "devScorer",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2026-04-24T10:56:23.076Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "neethus",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-09-10T21:33:01.424Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "devScorer",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2026-02-09T16:41:27.012Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "tsneddon",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T15:42:57.114Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "devScorer",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-02-09T16:39:55.100Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "cspecSviApproverTest",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2026-04-24T10:56:09.093Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"021"
],
"title": "ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACADVL Version 1.2.0",
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015",
"version": "1.2.0",
"versioned": true
},
"entId": "GN021",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "021_BP2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "021",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509401",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509401",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL5i---"
},
{
"entContent": {
"_uniqueProp": "021_BS2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": "Test",
"label": "BS2",
"ns": "021",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Analogous Gene"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Test",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509397",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509397",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gM-O---"
},
{
"entContent": {
"_uniqueProp": "021_BS1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "021",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Variants with a highest population minor allele frequency (MAF) ≥0.0035 (0.35%) in any continental population with >2000 alleles in gnomAD will meet BS1.\n* See Appendix 2 for calculations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509396",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509396",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL7G---"
},
{
"entContent": {
"_uniqueProp": "021_PP4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "021",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n* To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet:\n* PP4\\_moderate (Must meet at least one of the below criteria):\n * VLCAD enzyme activity (β-Oxidation Flux) ≤20% of normal.\n * Clinical plasma acylcarnitine testing, not from newborn screen, is consistent with VLCADD\n * NBS C14:1 Levels ≥ 1.0 μM AND:\n * VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal OR Assertion of reduced VLCAD activity without specific levels OR Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.\n* To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet: \n* PP4_supporting (Must meet at least one of the below criteria):\n * VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal.\n * Assertion of reduced VLCAD activity without specific levels.\n * NBS C14:1 Levels from >0.8 μM.\n * Assertion of abnormal NBS “consistent with VLCADD” without specific levels AND: Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509393",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509393",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL5C---"
},
{
"entContent": {
"_uniqueProp": "021_PM6_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "021",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509389",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509389",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL3G---"
},
{
"entContent": {
"_uniqueProp": "021_PS4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "021",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509383",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509383",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL4a---"
},
{
"entContent": {
"_uniqueProp": "021_PS2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "021",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 8,
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 4,
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 2,
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509381",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509381",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL7m---"
},
{
"entContent": {
"_uniqueProp": "021_BP6_nuclear_ACADVL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "021",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509405",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509405",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL9y---"
},
{
"entContent": {
"_uniqueProp": "021_BP4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "021",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Missense changes with a REVEL score <0.5 will meet BP4.\n* For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is a with Δ Score ≤ 0.2 , <10% reduction using MaxEntScn and <2% reduction using NNSplice. Two out of the three predictors must be consistent to count.\n* Do not apply this rule if there is evidence for creation of a cryptic splice site.\n* Can be used with BP7 code.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509403",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509403",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gM_q---"
},
{
"entContent": {
"_uniqueProp": "021_BP1_nuclear_ACADVL",
"additionalComments": "This rule does not apply. There are known pathogenic missense variants in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "021",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509400",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509400",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL1e---"
},
{
"entContent": {
"_uniqueProp": "021_BS3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "021",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "In vitro expression:\n * >50% enzyme activity\nSplicing assays:\n * For non-canonical splicing variants, use BS3 if there is evidence demonstrating normal splicing with no evidence of abnormal splicing (RT-PCR and/or RNA sequencing).\n * These studies can be performed using patient-derived cells or heterologous cultured cells.\n * Any variants meeting the requirement for in vitro expression or splicing assays can meet BS3, but if the variant meets the description for both, BS3 should only be counted once.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509398",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509398",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gMB----"
},
{
"entContent": {
"_uniqueProp": "021_BA1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "021",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"defaultPoint": "Not Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Variants with a highest population minor allele frequency (MAF) ≥0.007 (0.7%) in any continental population with >2000 alleles in gnomAD will meet BA1.\n* See Appendix 2 for calculations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509395",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509395",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL3e---"
},
{
"entContent": {
"_uniqueProp": "021_PP2_nuclear_ACADVL",
"additionalComments": "This rule does not apply as there are benign and pathogenic missense variants in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "021",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": 1,
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509391",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509391",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gMAi---"
},
{
"entContent": {
"_uniqueProp": "021_PM1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "021",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Examples of mutational hot spots:\nIt has been cited that the CpG dinucleotides in the codon for arginine326 and arginine429 are mutational hot spots, since CrT (R326C and R429W) and GrA (R326H and R429Q) mutations of the CpG di- nucleotide are present in both codons. Article for reference is Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency – by Andresen et al., 1999 (PMID 9973285).\n* Please refer to “Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain acyl-CoA Dehydrogenase” by McAndrew et al., 2008 (PMID 18227065) (note – numbering in this reference is for the mature peptide without the mitochondrial signal peptide, so amino acid position numbers are lower by 40 than numbering based on NM-000018.4) and “Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches” by Gobin-Limballe et al., 2010 (PMID 20060901) for identifying important structural regions for proper enzyme function such as binding sites and active sites of the enzyme. Based on this and information from UniProt the following regions are designated to be important functional domains:\n * p.214-223, p.249-251, p.460-466, p.562: Nucleotide and substrate binding.\n * p.481-516: Membrane binding.\n * p.1-40: Mitochondrial signal peptide.\n* Curators may seek approval from the expert panel for identifying new hot spots or critical regions as discovered in literature searches, in uniport, HGMD, etc. for inclusion.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509384",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509384",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL86---"
},
{
"entContent": {
"_uniqueProp": "021_PVS1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "021",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 8,
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., 2018; PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., 1995; PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift:\n\n* Use caution when interpreting LOF variants at the 3’ end of the gene.\n* All nonsense and frameshift variants will meet PVS1 unless the variant is predicted to be missed by nonsense-mediated decay (NMD).\n* NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). Canonical Splice Site (+1, +2, -1, -2):\n* All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood.\n* For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped. For the predicted in frame/out of frame consequences for exon skipping in ACADVL (NM\\_000018.4), see Appendix 1. Deletions:\n* For single or multi-exon deletions that result in an out-of-frame consequence, use PVS1 unless NMD is not predicted to occur. If NMD is not predicted to occur, use PVS1\\_Moderate.\n* If a deletion results in an in-frame consequence, the deletion must encompass one or more exons in order to apply PVS1. Consult Appendix 1 and the PVS1 decision tree to assign a strength. Duplications:\n* Single and multi-exon duplications have not been reported in ACADVL. Consult the PVS1 decision tree to assign the strength. Initiation codon:\n* The next in-frame methionine is at position 6 (on transcript NM\\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., 1995; PMID: 7668252). Therefore, initiator codon variants will meet PVS1\\_Strong.\n* If an in-frame deletion or splice variant disrupts a PM1 region, PVS1 can be modified to Strong instead of Moderate.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509379",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509379",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL9S---"
},
{
"entContent": {
"_uniqueProp": "021_BP5_nuclear_ACADVL",
"additionalComments": "An individual could be a carrier of a pathogenic variant in ACADVL and have another disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "021",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509404",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509404",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL8K---"
},
{
"entContent": {
"_uniqueProp": "021_BS4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "021",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -4,
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -1,
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509399",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509399",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gM_G---"
},
{
"entContent": {
"_uniqueProp": "021_PS3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "021",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Functional evidence from non-patient derived material with only a single variant best reflects the variant-level phenotype. Apply patient-derived evidence in PP4.\n* Apply criteria at the level determined by validation parameters (see flowchart below). VLCAD assays available now do not meet the criteria that is being proposed now regarding the types of controls etc. but the published VLCAD assays are well established with many positive and negative controls being run.\n* Hesse et al., 2018 (PMID 30194637) reviewed enzymatic testing in lymphocytes as a confirmatory tool in newborns identified by screening. Molecular testing was performed after in most patients.\n* If an enzyme activity assay has >20% activity it cannot be weighted above PS3_supporting regardless of flowchart results.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0045",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509382",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509382",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gM-u---"
},
{
"entContent": {
"_uniqueProp": "021_PS1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "021",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 4,
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Exact same donor/acceptor with a different nucleotide change (PMID: 37352859)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509380",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509380",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL2O---"
},
{
"entContent": {
"_uniqueProp": "021_BP7_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "021",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -4,
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": -2,
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": -1,
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Can be used with BP4 code.\n* Defined “not highly conserved” regions in BP7 as those with PhastCons score \\<1 and/or PhyloP score \\<0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.\n* BP7 to be applied to intronic variants at or beyond -21 and +7 (PMID: 37352859).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509406",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509406",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gMBy---"
},
{
"entContent": {
"_uniqueProp": "021_BP3_nuclear_ACADVL",
"additionalComments": "There are no known repetitive regions without known function in ACADVL.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "021",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -4,
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -2,
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"defaultPoint": -1,
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509402",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509402",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gMBi---"
},
{
"entContent": {
"_uniqueProp": "021_PP1_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "021",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Following SVI guidance, use the scoring system below to determine the strength of evidence for PP1.\n* For segregation counting, do not count probands as a segregation.\no Affected segregations = # affected individuals in the family with the variants - 1.\n* Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele.\n* Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant.\n* Unaffected, carrier parents DO NOT count as unaffected segregations.\n* There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509390",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509390",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL2y---"
},
{
"entContent": {
"_uniqueProp": "021_PM4_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "021",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509387",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509387",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL4K---"
},
{
"entContent": {
"_uniqueProp": "021_PM3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "021",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 8,
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.\n* If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.\n* Following SVI guidance for PM3, use the scoring system below to determine the strength of evidence for PM3.\n* These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.\n* For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509386",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509386",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL6a---"
},
{
"entContent": {
"_uniqueProp": "021_PP5_nuclear_ACADVL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "021",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509394",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509394",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gMAK---"
},
{
"entContent": {
"_uniqueProp": "021_PP3_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "021",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Missense changes with a REVEL score >0.75 will meet PP3.\n* For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is, a SpliceAI “high score” (Δ Score ≥ 0.5 “confidently predicted splice variants”) (exclude any results with Δ Score ≤ 0.2 from consideration of pathogenicity, <0.2 are not “predicted to alter splicing”), >15% reduction using MaxEntScn and >5% reduction using NNSplice. Two out of the three predictors must be consistent to count.\n* For SpliceAI’s cryptic splice-site rules, the creation of a new splice-site with Δ Score ≥ 0.5 may be enough to produce a large proportion of aberrant transcripts.\n* If a new splice site is predicted to be generated, this rule can be applied if the newly generated splice site is significantly stronger than the wild type site (Δ Score ≥ 0.5 using SpliceAI; >15% difference using MaxEntScn).\n* Do not apply this rule for canonical splice site changes meeting PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509392",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509392",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL8i---"
},
{
"entContent": {
"_uniqueProp": "021_PM5_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "021",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 4,
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 2,
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* These variant interpretation guidelines should be used to determine the classification of the other missense change in order to determine whether this rule can be applied.\n* Use PM5_Supporting if the other variant is Likely Pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 1,
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509388",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509388",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL56---"
},
{
"entContent": {
"_uniqueProp": "021_PM2_nuclear_ACADVL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"ACADVL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "021",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"defaultPoint": 2,
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"defaultPoint": 1,
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Variants with a highest population minor allele frequency (MAF) \\<0.001 (0.1%) in any continental population with >2000 alleles in gnomAD will meet PM2\\_supporting.\n* The 0.001 cutoff is based on a disease frequency of 1:100,000, genetic heterogeneity of 100%, penetrance of 75%, and maximum allelic contribution of 20%, based on the most common pathogenic ACADVL variant, c.848T>C (p.Val283Ala): gnomAD MAF: 0.002238 (289/129106; 1 homozygote; European Non-Finnish) and overall frequency: 0.001224 (346/282744; 2 homozygotes). This variant would not meet PM2\\_supporting, but it is assumed that the most common variants have already been identified so a conservative cutoff was chosen. The result of the calculation is 0.00073, which was multiplied by 1.5 to account for mild clinical presentation.\n* See Appendix 2 for calculations.\n* It is acceptable for an ACADVL variant to be present in controls because VLCAD deficiency is a recessive condition. It is also possible for homozygous ACADVL variants to be present in population databases due to later onset of the condition. If homozygous variants are present, the number should be noted and discussed with an expert.\n* SVI guidance: use PM2 as Supporting (not Moderate) based on absence or rarity not being in the odds range expected for a moderate piece of evidence. This EP will track the impact of not using Moderate for PM2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "639509385",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/639509385",
"modified": "2026-04-24T10:56:23.868Z",
"modifier": "devScorer",
"rev": "_lZ6gL6y---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0008723",
"lbl": "very long chain acyl-CoA dehydrogenase deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0008723"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/acyl_coa_dehydrogenase_very_long_chain_deficiency_of"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/907810567"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/854382"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/237997005"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3887523"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/E71.310"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080155"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C98647"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_26793"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/201475"
}
],
"definition": {
"val": "An inherited disorder of mitochondrial long-chain fatty acid oxidation with a variable presentation including: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.",
"xrefs": [
"Orphanet:26793"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "VLCAD",
"xrefs": [
"ICD10CM:E71.310",
"NCIT:C98647"
]
},
{
"pred": "hasExactSynonym",
"val": "VLCAD deficiency",
"xrefs": [
"DOID:0080155",
"OMIM:201475",
"Orphanet:26793"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "VLCADD",
"xrefs": [
"Orphanet:26793"
]
},
{
"pred": "hasExactSynonym",
"val": "Very Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)",
"xrefs": [
"NORD:1827"
]
},
{
"pred": "hasExactSynonym",
"val": "acyl-CoA dehydrogenase, very long-chain deficiency",
"xrefs": [
"NCIT:C98647"
]
},
{
"pred": "hasExactSynonym",
"val": "very long chain acyl-CoA dehydrogenase deficiency",
"xrefs": [
"DOID:0080155",
"Orphanet:26793",
"icd11.foundation:907810567"
]
},
{
"pred": "hasExactSynonym",
"val": "very long-chain acyl-CoA dehydrogenase deficiency",
"xrefs": [
"NCIT:C98647"
]
},
{
"pred": "hasExactSynonym",
"val": "very long-chain acyl-Coenzyme A dehydrogenase deficiency",
"xrefs": [
"NCIT:C98647"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "ACADVLD",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "acyl-CoA dehydrogenase, very long-chain, deficiency OF",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0080155"
},
{
"val": "GARD:5508"
},
{
"val": "ICD10CM:E71.310"
},
{
"val": "MEDGEN:854382"
},
{
"val": "NANDO:2200512"
},
{
"val": "NANDO:2201139"
},
{
"val": "NCIT:C98647"
},
{
"val": "NORD:1827"
},
{
"val": "OMIM:201475"
},
{
"val": "Orphanet:26793"
},
{
"val": "SCTID:237997005"
},
{
"val": "UMLS:C3887523"
},
{
"val": "icd11.foundation:907810567"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0008723",
"name": "very long chain acyl-CoA dehydrogenase deficiency"
},
"entId": "MONDO:0008723",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0008723",
"entType": "Disease",
"ldhId": "467878321",
"ldhIri": "https://genboree.org/cspec/Disease/id/467878321",
"modified": "2025-10-07T15:43:46.069Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vw92---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056941820510200,
"agr": "HGNC:92",
"alias_symbol": [
"VLCAD",
"LCACD",
"ACAD6"
],
"ccds_id": [
"CCDS11090",
"CCDS42249",
"CCDS58509"
],
"date_approved_reserved": "1996-05-30",
"date_modified": "2021-05-26",
"date_name_changed": "2017-09-21",
"ena": [
"BC012912"
],
"ensembl_gene_id": "ENSG00000072778",
"entrez_id": "37",
"gene_group": [
"Acyl-CoA dehydrogenase family"
],
"gene_group_id": [
974
],
"hgnc_id": "HGNC:92",
"location": "17p13.1",
"location_sortable": "17p13.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000356839.10",
"NM_000018.4"
],
"mgd_id": [
"MGI:895149"
],
"name": "acyl-CoA dehydrogenase very long chain",
"omim_id": [
"609575"
],
"orphanet": 117713,
"prev_name": [
"acyl-Coenzyme A dehydrogenase, very long chain"
],
"pubmed_id": [
8921384
],
"refseq_accession": [
"NM_000018"
],
"rgd_id": [
"RGD:2014"
],
"status": "Approved",
"symbol": "ACADVL",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002gev.5",
"uniprot_ids": [
"P49748"
],
"uuid": "aee49af3-48f6-4197-906b-bb0ea6a36ccf",
"vega_id": "OTTHUMG00000102157"
}
},
"entId": "ACADVL",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:92",
"entType": "Gene",
"ldhId": "467816115",
"ldhIri": "https://genboree.org/cspec/Gene/id/467816115",
"modified": "2021-10-14T11:36:28.156Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "021_nuclear_ACADVL",
"geneType": "nuclear",
"generalComments": "Version 1.1 ",
"genes": [
{
"diseases": [
{
"adjective": "None",
"modesOfInheritance": [
{
"adjective": "None",
"modeOfInheritance": "Autosomal recessive inheritance"
}
],
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0008723",
"preferredTitle": "very long chain acyl-CoA dehydrogenase deficiency"
}
],
"gene": "ACADVL",
"preferredTranscript": "NM_000018.4"
}
],
"ns": "021",
"references": [],
"rules": {
"pointRules": {
"items": [
{
"conditions": [
{
"condition": ">=10",
"label": "Rule1, Condition1"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"condition": ">=6",
"label": "Rule2, Condition2"
},
{
"condition": "<=9",
"label": "Rule2, Condition1"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"condition": ">=0",
"label": "Rule3, Condition1"
},
{
"condition": "<=5",
"label": "Rule3, Condition2"
}
],
"inference": "Uncertain Significance",
"rule": "Rule3"
},
{
"conditions": [
{
"condition": ">=-6",
"label": "Rule4, Condition1"
},
{
"condition": ">=-2",
"label": "Rule4, Condition2"
}
],
"inference": "Likely Benign",
"rule": "Rule4"
},
{
"conditions": [
{
"condition": "<=-7",
"label": "Rule5, Condition1"
}
],
"inference": "Benign",
"rule": "Rule5"
}
],
"notes": ""
}
},
"type": "Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015"
},
"entType": "RuleSet",
"ldhId": "639509377",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/639509377",
"modified": "2026-04-24T10:56:23.712Z",
"modifier": "devScorer",
"rev": "_lZ6gLrW---"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2019-03-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-03-12T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-11-08T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-01-19T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "ACADVL",
"shortBaseName": "ACADVL",
"shortTitle": "ACADVL VCEP",
"title": "ACADVL Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50048",
"entIri": "https://clinicalgenome.org/affiliation/50048",
"entType": "Organization",
"ldhId": "635003640",
"ldhIri": "https://genboree.org/cspec/Organization/id/635003640",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--Y"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "639509375",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/639509375",
"modified": "2026-04-24T10:56:23.582Z",
"modifier": "devScorer",
"rev": "_lZ6gLjK---"
},
{
"entContent": {
"approvedOn": "2022-01-05T00:00:00.000Z",
"description": "This version specified for the following genes: FBN1",
"namespace": "GN022",
"shortTitle": "FBN1 Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/docs/clingen-fbn1-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-01-05T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"022"
],
"title": "ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN022",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "022_BP1_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "022",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243127",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243127",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--J"
},
{
"entContent": {
"_uniqueProp": "022_PP5_nuclear_FBN1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "022",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243121",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243121",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK--I"
},
{
"entContent": {
"_uniqueProp": "022_PP4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "022",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Use if patient fulfils revised Ghent criteria.\n* Can be used if any of the family members have a highly specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243120",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243120",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--B"
},
{
"entContent": {
"_uniqueProp": "022_PM6_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequence-variant-interpretation/\n* The expert panel provided definitions for:\n ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1).\n ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes).\n ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life.\nThe EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD.",
"label": "PM6",
"ns": "022",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0014",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0037",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0022",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243116",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243116",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo2--A"
},
{
"entContent": {
"_uniqueProp": "022_BP4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "022",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Recommended prediction program for missense variants: REVEL. Use 0.326 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243130",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243130",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK--K"
},
{
"entContent": {
"_uniqueProp": "022_BS3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "022",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0072",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use the ‘Funtional Assay SVI Documentation’ (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).\nFor step 2 assessment.\n* Functional studies deemed appropriate:\n * cDNA analyses showing altered FBN1 sequence.\n * Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.\n* Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.\nFor step 3 assessment: Studies should be performed in the presence of NMD inhibitor.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243125",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243125",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxpG--I"
},
{
"entContent": {
"_uniqueProp": "022_BS2_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "022",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0069",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243124",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243124",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--D"
},
{
"entContent": {
"_uniqueProp": "022_BA1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "022",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.1% in ExAc and gnomAD\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243122",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243122",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpK--J"
},
{
"entContent": {
"_uniqueProp": "022_PP2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "022",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0061",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243118",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243118",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--I"
},
{
"entContent": {
"_uniqueProp": "022_PM1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "022",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0028",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Cys residues in cbEGF-like domains\n* Add caveat: PM5/PS1 should not be used when this argument applies.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Cys in EGF-like domain, Cys in TB domain, Cys in hybrid domain, (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) substitution in cbEGF-like domain, invariant calcium-binding or hydroxylation residue in cbEGF-like domain, critical Gly between Cys2-Cys3 in cbEGF-like domain, Gly between Cys3-Cys4 if there is an upstream cbEGF domain, Cys-creating variants.\n* Add caveat: N to S substitution in the second N of de consensus sequence and G to A might be tolerated, PM1 should not be used in these cases.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243111",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243111",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--G"
},
{
"entContent": {
"_uniqueProp": "022_PS3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "Use the ‘Funtional Assay SVI Documentation’ (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).\nFor step 2 assessment\n* Functional studies deemed appropriate:\n cDNA analyses showing altered FBN1 sequence.\n Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.\n* Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.\nFor step 3 assessment: Studies should be performed in the presence of NMD inhibitor.",
"label": "PS3",
"ns": "022",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Follow the ‘Funtional Assay SVI Documentation’",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow the ‘Funtional Assay SVI Documentation’",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the ‘Funtional Assay SVI Documentation’. ",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243109",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243109",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxo6--L"
},
{
"entContent": {
"_uniqueProp": "022_PS2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Use the SVI WG point-based system https://clinicalgenome.org/working-groups/sequence-variant-interpretation/\n* The expert panel provided definitions for:\n ‘highly specific phenotype’: TAAD + ectopia lentis (mainly caused by variants in FBN1).\n ‘consistent phenotype:’ TAAD + systemic score ≥7 (can be caused by variants in few other HTAD genes).\n ‘consistent but genetic heterogeneity’:(isolated) TAAD, isolated ectopia lentis and in case of a child (age <20yrs) systemic score≥ 7 in whom TAAD is progressive and can be developed later in life.\nThe EP recommends that the parents had a full clinical work-up and an echocardiogram to exclude MFS/HTAAD.",
"label": "PS2",
"ns": "022",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Four points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Two-three points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "One point",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243108",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243108",
"modified": "2022-08-30T14:08:37.772Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHxou--D"
},
{
"entContent": {
"_uniqueProp": "022_PVS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Follow the adapted flowchart.\n* There is only 1 relevant transcript for FBN1 (NM_000138).\n* The C-terminal region is proven to be critical to protein function (multiple LP/P variants identified in this region).\n* PP3 cannot be applied if using the PVS1criterion for splice site variants in position +/- ½.",
"label": "PVS1",
"ns": "022",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": " * Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD.\n * Full gene deletion.\n * Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD.\n * Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": " * Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon).\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD.\n * 1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame.\n * Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD.\n * Single to multi-exon deletion preserving the reading frame.\n * Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": " * Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243106",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243106",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--A"
},
{
"entContent": {
"_uniqueProp": "022_BP3_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "022",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243129",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243129",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--E"
},
{
"entContent": {
"_uniqueProp": "022_BS4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "022",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243126",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243126",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--M"
},
{
"entContent": {
"_uniqueProp": "022_BS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "022",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0070",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (>0.005%).\n* Use the ethnic population with the highest allele frequency.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243123",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243123",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--C"
},
{
"entContent": {
"_uniqueProp": "022_PP3_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "022",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Recommended prediction program for missense variants: REVEL. Use 0.75 as a discriminatory cut-off value.\n* Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243119",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243119",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--I"
},
{
"entContent": {
"_uniqueProp": "022_PP1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Only count affected individuals from the same family (minus proband) that carry the variant or obligate carriers known with the disease.\n* The EP will not specifically define “affected”, “clinical examination” or cut-offs for aortic Z-scores. These are left to the discretion of the referring physicians.",
"label": "PP1",
"ns": "022",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥5 affected individuals.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4 affected individuals.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "2-3 affected individuals.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243117",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243117",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--H"
},
{
"entContent": {
"_uniqueProp": "022_PM2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "022",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Threshold: <5.0E-6 (<0.0005%).\n* Use the highest ethnic population allele frequency.\n* Caveat: PVS1 + PM2_Supportive may reach Likely Pathogenic.\n* Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.\n* Minimum amount of studied alleles should be 2000.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243112",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243112",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--H"
},
{
"entContent": {
"_uniqueProp": "022_PS1_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "022",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles.\n* Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243107",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243107",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--F"
},
{
"entContent": {
"_uniqueProp": "022_BP7_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "022",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\nBP7 applicable as described.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243133",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243133",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--K"
},
{
"entContent": {
"_uniqueProp": "022_BP6_nuclear_FBN1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "022",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243132",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243132",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxpC--F"
},
{
"entContent": {
"_uniqueProp": "022_BP5_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "022",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0078",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243131",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243131",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--J"
},
{
"entContent": {
"_uniqueProp": "022_BP2_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "022",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Observed in trans in multiple cases (+2) with co-occuring pathogenic variants and phenotype is not more severe than when seen in isolation.\n* Observed in cis with a pathogenic variant, if the pathogenic variant has been seen in isolation in a patient with the disease phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243128",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243128",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--K"
},
{
"entContent": {
"_uniqueProp": "022_PM5_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "022",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Add caveat: Use argument with caution when the original missense variant created a cysteine especially in a cbEGFlike domain (cfr PM1_strong) as this may increase the\npathogenicity level of this variant improperly.\n* Add caveat: original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243115",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243115",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--L"
},
{
"entContent": {
"_uniqueProp": "022_PM4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "022",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Add caveat: cannot be applied simultaneously with PVS1 (at any strength level)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243114",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243114",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--G"
},
{
"entContent": {
"_uniqueProp": "022_PM3_nuclear_FBN1",
"additionalComments": "",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "022",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243113",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243113",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxo2--K"
},
{
"entContent": {
"_uniqueProp": "022_PS4_nuclear_FBN1",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"FBN1"
],
"geneType": "nuclear",
"instructionsToUse": "\n* Each additional proband meeting Ghent criteria or having ectopia lentis may receive 1 point while those having only thoracic aortic disease or high systemic score or those for which the phenotype is not described in the literature will receive 0.5 points. * Caveat: BA1/BS1 should not be met.",
"label": "PS4",
"ns": "022",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0053",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* If ≥ 4 points.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0057",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* If 2-3.5 points.\n",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0032",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* If 1-1.5 points.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243110",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243110",
"modified": "2022-03-24T11:34:33.560Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--F"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007947",
"lbl": "Marfan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3155"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4948"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6751"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007947"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/marfan_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0017311"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019755"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020208"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020211"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020236"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6975/marfan-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10026829"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/236564145"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/44287"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D008382"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/19346006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0024796"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/Q87.4"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_14323"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34807"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_284963"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_558"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/154700"
}
],
"definition": {
"val": "A disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). It is caused by mutations in the FBN1 gene, which provides instructions for making a protein called fibrillin-1. Marfan syndrome is inherited in an autosomal dominant pattern. At least 25% of cases are due to a new (de novo) mutation. Treatment is based on the signs and symptoms in each person.",
"xrefs": [
"https://rarediseases.info.nih.gov/diseases/6975/marfan-syndrome"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#prototype_pattern",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MFS",
"xrefs": [
"MONDO:Lexical",
"OMIM:154700",
"Orphanet:558"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MFS1",
"xrefs": [
"Orphanet:284963"
]
},
{
"pred": "hasExactSynonym",
"val": "Marfan syndrome",
"xrefs": [
"DOID:14323",
"MONDO:Lexical",
"NCIT:C34807",
"OMIM:154700",
"Orphanet:558",
"icd11.foundation:236564145"
]
},
{
"pred": "hasExactSynonym",
"val": "Marfan syndrome type 1",
"xrefs": [
"Orphanet:284963"
]
},
{
"pred": "hasExactSynonym",
"val": "Marfan syndrome, type 1",
"xrefs": [
"OMIM:154700"
]
},
{
"pred": "hasExactSynonym",
"val": "Marfan's syndrome",
"xrefs": [
"DOID:14323",
"NCIT:C34807"
]
}
],
"xrefs": [
{
"val": "DOID:14323"
},
{
"val": "GARD:16535"
},
{
"val": "ICD10CM:Q87.4"
},
{
"val": "ICD9:759.82"
},
{
"val": "MEDGEN:44287"
},
{
"val": "MESH:D008382"
},
{
"val": "MedDRA:10026829"
},
{
"val": "NANDO:1200644"
},
{
"val": "NANDO:2200968"
},
{
"val": "NCIT:C34807"
},
{
"val": "NORD:1403"
},
{
"val": "OMIM:154700"
},
{
"val": "Orphanet:284963"
},
{
"val": "Orphanet:558"
},
{
"val": "SCTID:19346006"
},
{
"val": "UMLS:C0024796"
},
{
"val": "icd11.foundation:236564145"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007947",
"name": "Marfan syndrome"
},
"entId": "MONDO:0007947",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007947",
"entType": "Disease",
"ldhId": "467897451",
"ldhIri": "https://genboree.org/cspec/Disease/id/467897451",
"modified": "2025-10-07T15:43:34.445Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Vlsy---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056947605504000,
"agr": "HGNC:3603",
"alias_name": [
"Marfan syndrome",
"asprosin"
],
"alias_symbol": [
"MASS",
"OCTD",
"SGS"
],
"ccds_id": [
"CCDS32232"
],
"date_approved_reserved": "1987-09-11",
"date_modified": "2021-05-26",
"date_name_changed": "2006-04-25",
"ena": [
"X63556"
],
"ensembl_gene_id": "ENSG00000166147",
"entrez_id": "2200",
"gene_group": [
"Fibrillins"
],
"gene_group_id": [
1888
],
"hgnc_id": "HGNC:3603",
"iuphar": "ligandId:9200",
"location": "15q21.1",
"location_sortable": "15q21.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"UMD Locus Specific Databases|http://www.umd.be/",
"LRG_778|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_778.xml"
],
"mane_select": [
"ENST00000316623.10",
"NM_000138.5"
],
"mgd_id": [
"MGI:95489"
],
"name": "fibrillin 1",
"omim_id": [
"134797"
],
"orphanet": 121752,
"prev_name": [
"fibrillin 1 (Marfan syndrome)"
],
"prev_symbol": [
"FBN",
"MFS1",
"WMS"
],
"pubmed_id": [
10036187,
12525539
],
"refseq_accession": [
"NM_000138"
],
"rgd_id": [
"RGD:620908"
],
"status": "Approved",
"symbol": "FBN1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001zwx.3",
"uniprot_ids": [
"P35555"
],
"uuid": "cfc89a21-2c25-4fd2-b826-2d42221c553d",
"vega_id": "OTTHUMG00000172218"
}
},
"entId": "FBN1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3603",
"entType": "Gene",
"ldhId": "467826222",
"ldhIri": "https://genboree.org/cspec/Gene/id/467826222",
"modified": "2021-10-14T11:36:38.697Z",
"modifier": "genbadmin",
"rev": "_h6SHyqW--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "022_nuclear_FBN1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0007947",
"preferredTitle": "Marfan syndrome"
}
],
"gene": "FBN1",
"preferredTranscript": "NM_000138"
}
],
"ns": "022",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243099",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243099",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--Z"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "FBN1",
"approval": {
"step1": {
"approvalDate": "2019-03-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-08-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-01-04T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-02-23T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "FBN1",
"shortBaseName": "FBN1",
"shortTitle": "FBN1 VCEP",
"title": "FBN1 Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50046",
"entIri": "http://clinicalgenome.org/affiliation/50046",
"entType": "Organization",
"ldhId": "639508883",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508883",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--M"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243092",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243092",
"modified": "2023-09-29T15:16:48.670Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--O"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN023",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"023"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1",
"version": "1.0.0"
},
"entId": "GN023",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "023_BP2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "023",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0084",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).\n* Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243156",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243156",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--D"
},
{
"entContent": {
"_uniqueProp": "023_PP4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "023",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0063",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).\n* The HL-EP applied this rule to HL syndromes if all causative genes have been sequenced and the detection rate at least doubles when the added clinical feature is present.\n* See table below for applicable gene-disease phenotypes.\n* Advise against using PP4 for patients with nonsyndromic or apparently nonsyndromic hearing loss, given genetic heterogeneity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243148",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243148",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--P"
},
{
"entContent": {
"_uniqueProp": "023_PP2_nuclear_OTOF_MYO15A",
"additionalComments": "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "023",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243146",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243146",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--A"
},
{
"entContent": {
"_uniqueProp": "023_BP6_nuclear_OTOF_MYO15A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "023",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243160",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243160",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy--_"
},
{
"entContent": {
"_uniqueProp": "023_BP3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "023",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable as originally described",
"id": "0081",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame indels in repeat region without known function.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243157",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243157",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--D"
},
{
"entContent": {
"_uniqueProp": "023_BS3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "023",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Functional study shows no deleterious effect (none are defined for OTOF and MYO15A).\n* Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n\n* No specific assays are listed for OTOF or MYO15A. However, BS3_Supporting can be used for functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.\n",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243153",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243153",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--C"
},
{
"entContent": {
"_uniqueProp": "023_PP3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "023",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0062",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.\n* Use REVEL and MAXENTSCAN\n * For missense variants, award PP3 if REVEL score is ≥0.7\n * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3\n* For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.\n * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243147",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243147",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--A"
},
{
"entContent": {
"_uniqueProp": "023_PM6_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "023",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0010",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 above.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243144",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243144",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--S"
},
{
"entContent": {
"_uniqueProp": "023_PS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "023",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0050",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.\n* Established variant must meet criteria for pathogenicity by the HL specifications.\n* Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant.\n * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.\n* No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.\n* Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243135",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243135",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--O"
},
{
"entContent": {
"_uniqueProp": "023_BP4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "023",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0080",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.\n* Use REVEL, award BP4 if score is 0.15 or lower. Make sure to also check MAXENTSCAN to rule out the creation of a cryptic splice site.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243158",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243158",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--U"
},
{
"entContent": {
"_uniqueProp": "023_BA1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "023",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"strengthDescriptor": [
{
"applicability": "Applicable with VCEP specification",
"id": "0087",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF of ≥0.005 (0.5%) for autosomal recessive.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243150",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243150",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--B"
},
{
"entContent": {
"_uniqueProp": "023_PP1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "023",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0023",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Segregation in three affected relatives for recessive.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0040",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Segregation in two affected relatives for recessive.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0060",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Segregation in one affected relative for recessive.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243145",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243145",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--T"
},
{
"entContent": {
"_uniqueProp": "023_PM5_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "023",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0056",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at same codon as two different pathogenic missense variants.\nLocated at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data).\n* Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "008",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at same codon as another pathogenic missense variant.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243143",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243143",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--Q"
},
{
"entContent": {
"_uniqueProp": "023_PM4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "023",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "009",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.\nNo changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243142",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243142",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--_"
},
{
"entContent": {
"_uniqueProp": "023_PS4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "023",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0029",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243138",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243138",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--M"
},
{
"entContent": {
"_uniqueProp": "023_BP7_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "023",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0079",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant with no predicted impact to splicing.\n* No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243161",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243161",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--V"
},
{
"entContent": {
"_uniqueProp": "023_BP5_nuclear_OTOF_MYO15A",
"additionalComments": "Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "023",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243159",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243159",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--E"
},
{
"entContent": {
"_uniqueProp": "023_BP1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "023",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243155",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243155",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoy---"
},
{
"entContent": {
"_uniqueProp": "023_BS4_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "023",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0071",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Non-segregation with disease.\n* Phenotype+/genotype-\n * Strong evidence for benign.\n * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:\n * Age of onset (ie. congenital/early childhood vs. adult onset)\n * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.\n * Severity (ie - mild vs. profound)\n * Minor differences may exist among family members.\n * Keep in mind that progression in older individuals may account for a discrepancy between individuals.\n * Audiogram shape\n * May not be completely consistent among family members even with same etiology.\n- Genotype+/phenotype-\n* Confounding variables to applying this rule: Age-related penetrance, variable expressivity, etc.\n* If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting\n.\n* Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss)\no Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).\n\n* Any evidence for reduced penetrance, do not use BS4.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243154",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243154",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--R"
},
{
"entContent": {
"_uniqueProp": "023_PM3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "023",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0038",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points awarded from tables 7a and 7b.\nExample: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0058",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points awarded from tables 7a and 7b.\nExample: Detected in trans in 2 probands with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "007",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point awarded from tables 7a and 7b\nExample: Detected in trans with a pathogenic variant (recessive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0027",
"instructionsToUse": "",
"specificationType": "Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points awarded from tables 7a and 7b\nExamples: \nTwo variants that meet PM2_Supporting detected in trans; OR\na homozygous variant meeting PM2_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243141",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243141",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--O"
},
{
"entContent": {
"_uniqueProp": "023_PM2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "023",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0030",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243140",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243140",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxoq--P"
},
{
"entContent": {
"_uniqueProp": "023_PS2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "023",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0016",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "4 points per tables 5a and 5b:\nExamples: 2 proven de novo occurrences; OR\n1 proven + 2 assumed de novo occurrences; OR\n4 assumed de novo occurrences.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0051",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2 points per tables 5a and 5b:\nExamples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.\n\n* OTOF and MYO15A are associated with autosomal recessive conditions. Therefore, de novo variants are expected to be an unlikely occurrence. It is recommended that de novo evidence is only awarded when phase with another variant (VUS, Likely Pathogenic, or Pathogenic) can be confirmed in trans. This is to avoid inappropriately awarding de novo evidence, which would lead to potentially incorrect classification.\n\n* Follow recommendations as specified by the Sequence Variant Interpretation working group within ClinGen, as outlined below\n \n* Determine number of points per proband using table 1 below. Sum the total number of points for all probands, and determine the strength of the evidence by using table 2.\n\n * Please note, the phenotype for de novo occurrences for MYO15A and OTOF are not considered “highly specific”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "004",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1 point per tables 5a and 5b:\nExamples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR\n1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0043",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 points per tables 5a and 5b:\nExample: 1 assumed de novo occurrence (phenotype/gene not specific).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243136",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243136",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--L"
},
{
"entContent": {
"_uniqueProp": "023_PVS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "023",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0017",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.\nPVS1 should also be considered for both of the genes OTOF and MYO15A with variants falling in two exons being exceptions to this rule: OTOF: NM_194248.2 Exon 46 (c.5841 to c.5994; PMID: 19250381) and MYO15A: NM_016239.3 Exon 8 (c.4033 to c. 4038; PMID: 10552926) and Exon 26 (c.5911 to c.5964; PMID: 30096381 and high frequency LOF variant https://gnomad.broadinstitute.org/variant/17-18046894-G-A?dataset=gnomad_r2_1)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0020",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0026",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "001",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243134",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243134",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--_"
},
{
"entContent": {
"_uniqueProp": "023_BS2_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "023",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0069",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.\n* Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.\n* However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable. Ensure age of the unaffected individual is appropriate. MYO15A and OTOF are expected to cause congenital or childhood onset hearing loss. Therefore, an adult (ie >18 years) may be an appropriate individual to consider application of this criteria. Please see additional considerations listed under BS4 “Genotype+/phenotype-”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243152",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243152",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--Q"
},
{
"entContent": {
"_uniqueProp": "023_BS1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "023",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0222",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "MAF of ≥0.003 (0.3%) for autosomal recessive. Likely benign, provided there is no conflicting evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0070",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0086",
"instructionsToUse": "",
"specificationType": "Disease-specific",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "MAF of ≥0.0007 (0.07%) for autosomal recessive.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243151",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243151",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxo6--C"
},
{
"entContent": {
"_uniqueProp": "023_PP5_nuclear_OTOF_MYO15A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "023",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243149",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243149",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO--B"
},
{
"entContent": {
"_uniqueProp": "023_PM1_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "023",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "006",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Mutational hot spot or well-studied functional domain without benign variation (None defined for OTOF and MYO15A).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243139",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243139",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxou--N"
},
{
"entContent": {
"_uniqueProp": "023_PS3_nuclear_OTOF_MYO15A",
"additionalComments": null,
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MYO15A",
"OTOF"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "023",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0052",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Knock-in mouse model demonstrates the phenotype.\n* Recommend that functional evidence, except for a variant specific mouse model, is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.\n* There are no specific assays for OTOF or MYO15A. However, PS3_Supporting can be applied for other functional analyses if\n * The assay has been validated by a known pathogenic and benign variant AND\n * There is plausible reason that the function the assay is testing relates to the phenotype AND\n * The assay conditions are likely to mimic the physiological environment.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0039",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Validated functional studies show a deleterious effect (none are defined for OTOF and MYO15A).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable with VCEP specification",
"id": "0045",
"instructionsToUse": "",
"specificationType": "None",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Functional studies with limited validation show a deleterious effect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243137",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243137",
"modified": "2022-05-23T18:09:21.055Z",
"modifier": "genbadmin",
"rev": "_h6SHxpO---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056956881207300,
"agr": "HGNC:8515",
"alias_name": [
"fer-1-like family member 2"
],
"alias_symbol": [
"FER1L2",
"DFNB6"
],
"ccds_id": [
"CCDS46241",
"CCDS1725",
"CCDS74497",
"CCDS1726",
"CCDS1724"
],
"date_approved_reserved": "1999-03-31",
"date_modified": "2021-05-26",
"ena": [
"AF107403"
],
"ensembl_gene_id": "ENSG00000115155",
"entrez_id": "9381",
"gene_group": [
"Ferlin family"
],
"gene_group_id": [
828
],
"hgnc_id": "HGNC:8515",
"location": "2p23.3",
"location_sortable": "02p23.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=OTOF"
],
"mane_select": [
"ENST00000272371.7",
"NM_194248.3"
],
"mgd_id": [
"MGI:1891247"
],
"name": "otoferlin",
"omim_id": [
"603681"
],
"orphanet": 124035,
"prev_symbol": [
"DFNB9"
],
"pubmed_id": [
10192385,
18381613
],
"refseq_accession": [
"NM_001287489"
],
"rgd_id": [
"RGD:620646"
],
"status": "Approved",
"symbol": "OTOF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002rhk.3",
"uniprot_ids": [
"Q9HC10"
],
"uuid": "e0ea26b4-7792-4b43-accc-e607201cc26d",
"vega_id": "OTTHUMG00000096977"
}
},
"entId": "OTOF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8515",
"entType": "Gene",
"ldhId": "467844034",
"ldhIri": "https://genboree.org/cspec/Gene/id/467844034",
"modified": "2021-10-14T11:36:56.997Z",
"modifier": "genbadmin",
"rev": "_h6SHzmS--I"
},
{
"entContent": {
"HGNC": {
"_version_": 1704056955121696800,
"agr": "HGNC:7594",
"ccds_id": [
"CCDS42271"
],
"date_approved_reserved": "1998-05-29",
"date_modified": "2021-05-26",
"ena": [
"AF144094"
],
"ensembl_gene_id": "ENSG00000091536",
"entrez_id": "51168",
"gene_group": [
"Myosin heavy chains, class XV",
"FERM domain containing"
],
"gene_group_id": [
1105,
1293
],
"hgnc_id": "HGNC:7594",
"location": "17p11.2",
"location_sortable": "17p11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000647165.2",
"NM_016239.4"
],
"mgd_id": [
"MGI:1261811"
],
"name": "myosin XVA",
"omim_id": [
"602666"
],
"orphanet": 123641,
"prev_symbol": [
"DFNB3",
"MYO15"
],
"pubmed_id": [
9603736
],
"refseq_accession": [
"NM_016239"
],
"rgd_id": [
"RGD:1561873"
],
"status": "Approved",
"symbol": "MYO15A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc060cbc.1",
"uniprot_ids": [
"Q9UKN7"
],
"uuid": "36cbba76-4372-4b96-be9b-ca52c1a9053e",
"vega_id": "OTTHUMG00000059390"
}
},
"entId": "MYO15A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7594",
"entType": "Gene",
"ldhId": "467841177",
"ldhIri": "https://genboree.org/cspec/Gene/id/467841177",
"modified": "2021-10-14T11:36:54.363Z",
"modifier": "genbadmin",
"rev": "_h6SHzpK--K"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "023_nuclear_OTOF_MYO15A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO15A",
"preferredTranscript": "NM_016239.3"
},
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "OTOF",
"preferredTranscript": "NM_194248.2"
}
],
"ns": "023",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243100",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243100",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--b"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN065",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:29.942Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"065"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO15A Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN065",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243135",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243135",
"modified": "2022-08-18T19:14:33.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN066",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:33.937Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"066"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN066",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243136",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243136",
"modified": "2022-08-18T19:14:37.292Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--B"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243093",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243093",
"modified": "2023-09-29T15:16:48.775Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--A"
},
{
"entContent": {
"approvedOn": "2024-01-30T20:28:04.228Z",
"description": "1. BA1/BS1/PM2 Clarification: In light of the recent release of gnomAD v4.0.0 without a (non-cancer) filter, removed the (non-cancer) text and added the following clarifying instruction: \"In general, the most recent/most comprehensive gnomAD version should be used.\"\n2. Criteria Combination Clarification: Added a general comment to the C Spec asking users to disregard the \"Rules for Combining Criteria\" section and instead use the \"Evidence Criteria Combinations\" table.",
"namespace": "GN024",
"releaseNotes": "1\\. BA1/BS1/PM2 Clarification: In light of the recent release of gnomAD v4.0.0 without a (non-cancer) filter, removed the (non-cancer) text and added the following clarifying instruction: \"In general, the most recent/most comprehensive gnomAD version should be used.\" \n2\\. Criteria Combination Clarification: Added a general comment to the C Spec asking users to disregard the \"Rules for Combining Criteria\" section and instead use the \"Evidence Criteria Combinations\" table.",
"releasedUnderRevision": true,
"shortTitle": "DICER1 and miRNA-Processing Gene Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "dagherjn",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-01-30T20:28:04.228Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "dagherjn",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-01-12T14:05:36.850Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "dagherjn",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-12T14:22:54.865Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-30T17:13:33.713Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"024"
],
"title": "ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0",
"version": "1.3.0",
"versioned": true
},
"entId": "GN024",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "024_BP1_nuclear_DICER1",
"additionalComments": "This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "024",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243183",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243183",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxq---H"
},
{
"entContent": {
"_uniqueProp": "024_PP3_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "PP3",
"ns": "024",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243175",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243175",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpi--B"
},
{
"entContent": {
"_uniqueProp": "024_PP2_nuclear_DICER1",
"additionalComments": "While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "024",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243174",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243174",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpi--F"
},
{
"entContent": {
"_uniqueProp": "024_PM6_nuclear_DICER1",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "024",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243172",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243172",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqC--F"
},
{
"entContent": {
"_uniqueProp": "024_BP6_nuclear_DICER1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "024",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243188",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243188",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxq---K"
},
{
"entContent": {
"_uniqueProp": "024_BP4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "BP4",
"ns": "024",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "For missense variants, REVEL score \\< 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243186",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243186",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxq---J"
},
{
"entContent": {
"_uniqueProp": "024_PP5_nuclear_DICER1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "024",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243177",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243177",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpi--D"
},
{
"entContent": {
"_uniqueProp": "024_PM3_nuclear_DICER1",
"additionalComments": "Autosomal dominant.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "024",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243169",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243169",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--Y"
},
{
"entContent": {
"_uniqueProp": "024_PM2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "PM2",
"ns": "024",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Allele frequency \\<0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20x coverage.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243168",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243168",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpm--F"
},
{
"entContent": {
"_uniqueProp": "024_PS2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",
"label": "PS2",
"ns": "024",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥4 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥2 but less than 4 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "≥1 but less than 2 de novo points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "≥0.5 but less than 1 de novo points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243164",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243164",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqG---"
},
{
"entContent": {
"_uniqueProp": "024_BP7_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "024",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant\nOR Intronic variant at or beyond +7 to -21 positions\nOR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.\nCaveat: Variant must meet BP4 to apply BP7",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243189",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243189",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpi--E"
},
{
"entContent": {
"_uniqueProp": "024_BS3_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.",
"label": "BS3",
"ns": "024",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018[7](#pmid_28862265).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243181",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243181",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpm--D"
},
{
"entContent": {
"_uniqueProp": "024_PM4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "024",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243170",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243170",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--T"
},
{
"entContent": {
"_uniqueProp": "024_PS3_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.",
"label": "PS3",
"ns": "024",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3\\_Moderate if PVS1\\_Strong is applied).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "RNA assay shows in-frame splicing impact with change in protein length \\<193 residues AND RNase IIIb domain not disrupted.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243165",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243165",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqG--C"
},
{
"entContent": {
"_uniqueProp": "024_PVS1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "024",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018[1](#pmid_30192042), the following will apply:\n\n* Nonsense or frameshift variants:\n* PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.\n* PVS1\\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff\n* Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:\n* Exon 10 SDS/SAS: PVS1\\_Strong (in-frame but exon includes >10% protein)\n* Exons 5, 15, 18, 22 SDS/SAS: PVS1\\_Moderate (in-frame and each \\<10% of protein)\n* Exon 27 SAS: PVS1\\_Moderate (final exon)\n* Exon 1: no criteria (non-coding)\n* Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243162",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243162",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--W"
},
{
"entContent": {
"_uniqueProp": "024_BP5_nuclear_DICER1",
"additionalComments": "Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "024",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243187",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243187",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpm--C"
},
{
"entContent": {
"_uniqueProp": "024_BP3_nuclear_DICER1",
"additionalComments": "Not applicable at this time.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "024",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243185",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243185",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpy--C"
},
{
"entContent": {
"_uniqueProp": "024_BS4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "024",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243182",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243182",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpK---"
},
{
"entContent": {
"_uniqueProp": "024_PP1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) Do not apply PP1 if variant meets BA1/BS1 criteria.",
"label": "PP1",
"ns": "024",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥7 meioses across ≥2 families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5 – 6 meioses across ≥1 family",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3 – 4 meioses across ≥1 family",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243173",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243173",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqG--_"
},
{
"entContent": {
"_uniqueProp": "024_PS4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset) Caveats:\n\n* Do not apply PS4 if variant meets BA1/BS1 criteria.\n* Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).\n* Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma[2](#pmid_25022261), pituitary blastoma[3](#pmid_24839956), and lung cysts or cystic nephroma lacking mesenchymal cells[4](#pmid_25500911),[5](#pmid_25978641) should not exclude the proband from PS4.",
"label": "PS4",
"ns": "024",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "≥4 phenotype points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2 – 3.5 phenotype points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 – 1.5 phenotype points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243166",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243166",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqG--A"
},
{
"entContent": {
"_uniqueProp": "024_BP2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "024",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥1 observation in trans with P/LP DICER1 variant or ≥3\nobservations in cis or phase unknown with 2+ different\nP/LP DICER1 variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243184",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243184",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--S"
},
{
"entContent": {
"_uniqueProp": "024_BS2_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "024",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) \nOR 2+ observations of homozygosity in healthy individuals\nOR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) \nOR 2+ observations of homozygosity in individuals lacking clinical information",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243180",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243180",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpm--E"
},
{
"entContent": {
"_uniqueProp": "024_BS1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "BS1",
"ns": "024",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Frequency >0.0003 (0.03%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243179",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243179",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxqG--B"
},
{
"entContent": {
"_uniqueProp": "024_BA1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "In general, the most recent/most comprehensive gnomAD version should be used.",
"label": "BA1",
"ns": "024",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Frequency >0.003 (0.3%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243178",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243178",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--X"
},
{
"entContent": {
"_uniqueProp": "024_PP4_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "024",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing[6](#pmid_30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:\n\n* A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND\n* Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:\n* The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR\n* Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243176",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243176",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxq---I"
},
{
"entContent": {
"_uniqueProp": "024_PM5_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "PM5",
"ns": "024",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243171",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243171",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpi--C"
},
{
"entContent": {
"_uniqueProp": "024_PM1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "024",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243167",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243167",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--U"
},
{
"entContent": {
"_uniqueProp": "024_PS1_nuclear_DICER1",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"DICER1"
],
"geneType": "nuclear",
"instructionsToUse": "All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites))",
"label": "PS1",
"ns": "024",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.\nThis rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243163",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243163",
"modified": "2024-01-30T20:28:04.971Z",
"modifier": "dagherjn",
"rev": "_h6SHxpG--V"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100216",
"lbl": "DICER1-related tumor predisposition",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5779"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6460"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100216"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/dicer1_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/dicer1_tumor_predisposition"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10734/dicer1-related-pleuropulmonary-blastoma-cancer-predisposition-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/825667"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702411003"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3839822"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0081063"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C123317"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_284343"
}
],
"definition": {
"val": "Pathogenic germline variation in DICER1 confers an autosomal dominant predisposition to tumor formation at multiple primary sites, including pleuropulmonary blastoma, pulmonary cysts, thyroid gland neoplasia, ovarian tumors, and cystic nephroma. Other syndromic features such as macrocephaly have been described.",
"xrefs": [
"PMID:21266384",
"PMID:24761742",
"PMID:34599283",
"https://clinicalgenome.org/affiliation/40023/",
"https://clinicalgenome.org/affiliation/50050/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "DICER1 syndrome",
"xrefs": [
"DOID:0081063",
"GARD:0010734",
"NCIT:C123317"
]
},
{
"pred": "hasExactSynonym",
"val": "PPB familial tumor susceptibility syndrome",
"xrefs": [
"DOID:0081063"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "PPB familial tumour susceptibility syndrome"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PPBFTDS",
"xrefs": [
"Orphanet:284343"
]
},
{
"pred": "hasExactSynonym",
"val": "pleuro-pulmonary blastoma familial tumor susceptibility syndrome",
"xrefs": [
"DOID:0081063"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "pleuro-pulmonary blastoma familial tumour susceptibility syndrome"
},
{
"pred": "hasExactSynonym",
"val": "pleuropulmonary blastoma familial tumor susceptibility syndrome",
"xrefs": [
"DOID:0081063"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "pleuropulmonary blastoma familial tumour susceptibility syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "DICER1-related pleuropulmonary blastoma",
"xrefs": [
"GARD:0010734"
]
},
{
"pred": "hasRelatedSynonym",
"val": "DICER1-related pleuropulmonary blastoma cancer predisposition syndrome",
"xrefs": [
"GARD:0010734"
]
}
],
"xrefs": [
{
"val": "DOID:0081063"
},
{
"val": "GARD:10734"
},
{
"val": "ICD9:199.1"
},
{
"val": "MEDGEN:825667"
},
{
"val": "NCIT:C123317"
},
{
"val": "Orphanet:284343"
},
{
"val": "SCTID:702411003"
},
{
"val": "UMLS:C3839822"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100216",
"name": "DICER1-related tumor predisposition"
},
"entId": "MONDO:0100216",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100216",
"entType": "Disease",
"ldhId": "1571068601",
"ldhIri": "https://genboree.org/cspec/Disease/id/1571068601",
"modified": "2025-10-07T15:48:31.234Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aHpq---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0017288",
"lbl": "obsolete DICER1 syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/MONDO_TermsMerged"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6460"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0100001",
"val": "http://purl.obolibrary.org/obo/MONDO_0100216"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0009068"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#otar"
],
"xrefs": [
{
"val": "EFO:0009068"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0017288",
"name": "obsolete DICER1 syndrome"
},
"entId": "MONDO:0017288",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0017288",
"entType": "Disease",
"ldhId": "467897091",
"ldhIri": "https://genboree.org/cspec/Disease/id/467897091",
"modified": "2025-10-07T15:46:05.826Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7X5su---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056945945608200,
"agr": "HGNC:17098",
"alias_name": [
"dicer 1, double-stranded RNA-specific endoribonuclease"
],
"alias_symbol": [
"Dicer",
"KIAA0928",
"K12H4.8-LIKE",
"HERNA"
],
"ccds_id": [
"CCDS55941",
"CCDS9931"
],
"cosmic": "DICER1",
"date_approved_reserved": "2002-05-09",
"date_modified": "2021-05-26",
"date_name_changed": "2016-03-24",
"ena": [
"AB028449"
],
"ensembl_gene_id": "ENSG00000100697",
"entrez_id": "23405",
"gene_group": [
"RNA helicases",
"Endoribonucleases",
"MicroRNA protein coding host genes",
"RISC loading complex"
],
"gene_group_id": [
1168,
1687,
1691,
1776
],
"hgnc_id": "HGNC:17098",
"location": "14q32.13",
"location_sortable": "14q32.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_492|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_492.xml"
],
"mane_select": [
"ENST00000343455.8",
"NM_177438.3"
],
"mgd_id": [
"MGI:2177178"
],
"name": "dicer 1, ribonuclease III",
"omim_id": [
"606241"
],
"orphanet": 209285,
"prev_name": [
"Dicer1, Dcr-1 homolog (Drosophila)",
"multinodular goitre 1",
"dicer 1, ribonuclease type III"
],
"prev_symbol": [
"MNG1"
],
"pubmed_id": [
10051563,
10786632,
21205968
],
"refseq_accession": [
"NM_030621"
],
"rgd_id": [
"RGD:1309381"
],
"status": "Approved",
"symbol": "DICER1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001ydw.3",
"uniprot_ids": [
"Q9UPY3"
],
"uuid": "820c84e2-0dd4-4701-9161-49a9564b34ae",
"vega_id": "OTTHUMG00000166134"
}
},
"entId": "DICER1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:17098",
"entType": "Gene",
"ldhId": "467823568",
"ldhIri": "https://genboree.org/cspec/Gene/id/467823568",
"modified": "2021-10-14T11:36:36.055Z",
"modifier": "genbadmin",
"rev": "_h6SHyYu--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "024_nuclear_DICER1",
"geneType": "nuclear",
"generalComments": "Please note that the DICER1 VCEP utilizes a Bayesian points system for final classification. Please disregard the \"Rules for Combining Criteria\" section of the C Spec and instead use the \"Evidence Criteria Combinations\" table at the bottom of the page. For more information about the Bayesian points combination, please see our open access publication: https://www.hindawi.com/journals/humu/2023/9537832/",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100216",
"preferredTitle": "DICER1-related tumor predisposition"
}
],
"gene": "DICER1",
"preferredTranscript": "NM_177438.2"
}
],
"ns": "024",
"references": [
{
"auths": [
"Abou Tayoun AN",
"Pesaran T",
"et al."
],
"doiStr": "10.1002/humu.23626",
"id": "30192042",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1517-1524.",
"source": "Hum Mutat",
"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"de Kock L",
"Sabbaghian N",
"et al."
],
"doiStr": "10.1007/s00401-014-1318-7",
"id": "25022261",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. 583-95.",
"source": "Acta Neuropathol",
"title": "Germ-line and somatic DICER1 mutations in pineoblastoma.",
"vol": "128",
"year": "2014"
},
{
"auths": [
"de Kock L",
"Sabbaghian N",
"et al."
],
"doiStr": "10.1007/s00401-014-1285-z",
"id": "24839956",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 111-22.",
"source": "Acta Neuropathol",
"title": "Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.",
"vol": "128",
"year": "2014"
},
{
"auths": [
"Wagh PK",
"Gardner MA",
"et al."
],
"doiStr": "10.1002/path.4500",
"id": "25500911",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 41-52.",
"source": "J Pathol",
"title": "Cell- and developmental stage-specific Dicer1 ablation in the lung epithelium models cystic pleuropulmonary blastoma.",
"vol": "236",
"year": "2015"
},
{
"auths": [
"Yin Y",
"Castro AM",
"et al."
],
"doiStr": "10.1371/journal.pgen.1005242",
"id": "25978641",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. e1005242.",
"source": "PLoS Genet",
"title": "Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma.",
"vol": "11",
"year": "2015"
},
{
"auths": [
"Walsh MF",
"Ritter DI",
"et al."
],
"doiStr": "10.1002/humu.23640",
"id": "30311369",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1542-1552.",
"source": "Hum Mutat",
"title": "Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"Wu MK",
"Vujanic GM",
"et al."
],
"doiStr": "10.1038/modpathol.2017.100",
"id": "28862265",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 169-178.",
"source": "Mod Pathol",
"title": "Anaplastic sarcomas of the kidney are characterized by DICER1 mutations.",
"vol": "31",
"year": "2018"
},
{
"auths": [
"de Kock L",
"Wu MK",
"et al."
],
"doiStr": "10.1002/humu.23877",
"id": "31342592",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1939-1953.",
"source": "Hum Mutat",
"title": "Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes.",
"vol": "40",
"year": "2019"
},
{
"auths": [
"Wu MK",
"Sabbaghian N",
"et al."
],
"doiStr": "10.1002/path.4196",
"id": "23620094",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 154-64.",
"source": "J Pathol",
"title": "Biallelic DICER1 mutations occur in Wilms tumours.",
"vol": "230",
"year": "2013"
},
{
"auths": [
"Gadd S",
"Huff V",
"et al."
],
"doiStr": "10.1038/ng.3940",
"id": "28825729",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 1487-1494.",
"source": "Nat Genet",
"title": "A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.",
"vol": "49",
"year": "2017"
},
{
"auths": [
"Tavtigian SV",
"Harrison SM",
"et al."
],
"doiStr": "10.1002/humu.24088",
"id": "32720330",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 1734-1737.",
"source": "Hum Mutat",
"title": "Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.",
"vol": "41",
"year": "2020"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule17"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243101",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243101",
"modified": "2024-01-30T20:28:04.863Z",
"modifier": "dagherjn",
"rev": "_h6SHyTK--T"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "DICER1",
"approval": {
"step1": {
"approvalDate": "2019-07-22T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-11-12T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-05-05T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-06-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "DICER1 and miRNA-Processing Gene",
"shortBaseName": "DICER1",
"shortTitle": "DICER1 and miRNA-Processing Gene VCEP",
"title": "DICER1 and miRNA-Processing Gene Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50050",
"entIri": "http://clinicalgenome.org/affiliation/50050",
"entType": "Organization",
"ldhId": "639508885",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508885",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--N"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243094",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243094",
"modified": "2024-01-30T20:28:04.789Z",
"modifier": "dagherjn",
"rev": "_h6SHykK--G"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:50:05.277Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for GATM (arginine:glycine amidinotransferase) Summary of ACMG-AMP Criteria for GATM Variants",
"namespace": "GN025",
"releaseNotes": "* Added supporting strength for PM3 and PM4. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:50:05.277Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T16:59:34.069Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2022-09-07T17:54:55.689Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:54:02.758Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:22.515Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"025"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN025",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "025_BP5_nuclear_GATM",
"additionalComments": "Variant found in a case with an alternate molecular basis for disease.\nCCDS VCEP notes for BP5: An individual could be a carrier of a pathogenic variant in GATM and have another disorder",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "025",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243215",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243215",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpG--K"
},
{
"entContent": {
"_uniqueProp": "025_BP2_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for BP1: Does not apply. All types of variants cause AGAT-D",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "025",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\nGATM specifications:\nObserved in cis with a pathogenic variant (to take AR inheritance into account).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243212",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243212",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--I"
},
{
"entContent": {
"_uniqueProp": "025_BS2_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "025",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243208",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243208",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--F"
},
{
"entContent": {
"_uniqueProp": "025_PM6_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "025",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243200",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243200",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--D"
},
{
"entContent": {
"_uniqueProp": "025_PS4_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "025",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243194",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243194",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--H"
},
{
"entContent": {
"_uniqueProp": "025_PS2_nuclear_GATM",
"additionalComments": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "025",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243192",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243192",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--A"
},
{
"entContent": {
"_uniqueProp": "025_PS1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "025",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* This criterion is applicable as described.\n* If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243191",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243191",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--B"
},
{
"entContent": {
"_uniqueProp": "025_BP3_nuclear_GATM",
"additionalComments": "In-frame deletions/insertions in a repetitive region without a known function.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "025",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243213",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243213",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpO--N"
},
{
"entContent": {
"_uniqueProp": "025_BP1_nuclear_GATM",
"additionalComments": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "025",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243211",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243211",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpG--L"
},
{
"entContent": {
"_uniqueProp": "025_BS4_nuclear_GATM",
"additionalComments": "Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "025",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243210",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243210",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--E"
},
{
"entContent": {
"_uniqueProp": "025_PP5_nuclear_GATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "025",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243205",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243205",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp----"
},
{
"entContent": {
"_uniqueProp": "025_PP2_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PP2:\nDoes not apply; there are benign and pathogenic missense variants in GATM.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "025",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243202",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243202",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--G"
},
{
"entContent": {
"_uniqueProp": "025_BP6_nuclear_GATM",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "025",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243216",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243216",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpG--J"
},
{
"entContent": {
"_uniqueProp": "025_BP4_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for BP3: There are no known repetitive regions without known function in GATM.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "025",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* REVEL score <0.15 for missense variants.\n* In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.\n* No predicted impact on splicing by SpliceAI and varSEAK.\nGATM specifications:\n* For missense changes, REVEL score <0.15.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use SpliceAI (https://spliceailookup.broadinstitute.org/ ) and varSEAK (https://varseak.bio/) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243214",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243214",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--_"
},
{
"entContent": {
"_uniqueProp": "025_BS3_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "025",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**\\>30% normal GAA activity when the variant is expressed in a heterologous cell type.** \nGATM specifications: \nIn vitro assays in which a variant is expressed in AGAT-deficient cultured cells (e.g. AGAT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GATM transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of AGAT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in DesRoches et al, 2016, PMID 27233232, meets BS3\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243209",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243209",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS---"
},
{
"entContent": {
"_uniqueProp": "025_PP4_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "025",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4 or more points based on any combination of the following. Two or more data types are required to meet Strong: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points) \n• AGAT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength. \n\\* For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 points based on any combination of the following. Two or more data types are recommended to reach moderate: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points) \n• AGAT enzyme activity \\<5% of normal (3 points)\n\nVariant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-2 points based on: \n• Low urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Low plasma guanidinoacetate with or without low or low normal creatine (2 points) \nVariant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243204",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243204",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpG--M"
},
{
"entContent": {
"_uniqueProp": "025_PM5_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "025",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243199",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243199",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---_"
},
{
"entContent": {
"_uniqueProp": "025_PM1_nuclear_GATM",
"additionalComments": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "025",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243195",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243195",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--_"
},
{
"entContent": {
"_uniqueProp": "025_PVS1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "025",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Nonsense-mediated decay predicted.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In frame loss of >10% of the protein.** \nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\nGATM specifications: \n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein, and initiator codon variants.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). \n\nGATM specifications:\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\\_Moderate will be applied.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GATM are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Initiator codon variants** \n\\* To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur. \n\\* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP\\_001473).\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243190",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243190",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--C"
},
{
"entContent": {
"_uniqueProp": "025_BP7_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "025",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243217",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243217",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--E"
},
{
"entContent": {
"_uniqueProp": "025_PP3_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "025",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* REVEL score >0.75 for missense variants.\n* In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.\n* Predicted impact on splicing by SpliceAI and varSEAK. GATM specifications:\n* For missense changes, those with a REVEL score more than 0.75 will meet PP3.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), use SpliceAI (([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)). Results must be consistent to apply this criterion.\n* For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.\n* Do not apply this rule for canonical splice site changes meeting PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243203",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243203",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK---"
},
{
"entContent": {
"_uniqueProp": "025_PM4_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "025",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "CCDS VCEP notes: Stop loss variants in GATM have not been reported, as far as we are aware. \n\nGATM specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Downgrade to PM4\\_Supporting for in frame deletion/insertion of a single amino acid.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243198",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243198",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo6--M"
},
{
"entContent": {
"_uniqueProp": "025_PM2_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "025",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Allele frequency \\<0.000055 (\\<0.0055%) in all populations in gnomAD.**\n\nCCDS VCEP notes: It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%. \n\nGATM specifications:\n\n* All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.\n* If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243196",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243196",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--B"
},
{
"entContent": {
"_uniqueProp": "025_PS3_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "025",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.**\n\nGATM specifications: \nAny variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once.\n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**\\<15% control activity when variant is expressed in HeLa cells, as reported in PMID 27233232.** \n**RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.**\n\nGATM specifications: \nAny variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once. \n\n**In vitro expression** \nAGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3\\_Supporting (see [Appendix 2](https://docs.google.com/spreadsheets/d/1ANaK1am_4svqc0h0m3qaEqLmjqTfJ0pG/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) for further details on AGAT functional assays). \n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243193",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243193",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--D"
},
{
"entContent": {
"_uniqueProp": "025_BS1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "025",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**Allele frequency >0.0001 (0.01%) in gnomAD in any continental population in gnomAD with >2000 alleles.**\n\n* Any variant with a frequency >0.0001 (max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) in a continental population with >2000 (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383) (see Appendix 3).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243207",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243207",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--A"
},
{
"entContent": {
"_uniqueProp": "025_BA1_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "025",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "**Allele frequency >0.0005 (0.05%) in gnomAD in any continental population in gnomAD with >2000 alleles.**\n\n* Any variant with a frequency >0.0005 (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) in a continental population with >2000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243206",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243206",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--F"
},
{
"entContent": {
"_uniqueProp": "025_PP1_nuclear_GATM",
"additionalComments": "CCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GATM is the only gene involved in AGAT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "025",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243201",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243201",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--C"
},
{
"entContent": {
"_uniqueProp": "025_PM3_nuclear_GATM",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GATM"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "025",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243197",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243197",
"modified": "2022-09-14T20:50:05.976Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---A"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012996",
"lbl": "AGAT deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012996"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/cerebral_creatine_deficiency_syndrome_3"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/436367"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C567192"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702440000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2675179"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050712"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_35704"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/612718"
}
],
"definition": {
"val": "L-Arginine:glycine amidinotransferase (AGAT) deficiency is a very rare type of creatine deficiency sydrome characterized by global developmental delay, intellectual disability, and myopathy.",
"xrefs": [
"Orphanet:35704"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "AGAT deficiency",
"xrefs": [
"DOID:0050712",
"OMIM:612718",
"Orphanet:35704"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CCDS3",
"xrefs": [
"OMIM:612718"
]
},
{
"pred": "hasExactSynonym",
"val": "GATM deficiency",
"xrefs": [
"OMIM:612718"
]
},
{
"pred": "hasExactSynonym",
"val": "L-arginine:glycine amidinotransferase deficiency",
"xrefs": [
"Orphanet:35704"
]
},
{
"pred": "hasExactSynonym",
"val": "arginine:glycine amidinotransferase deficiency",
"xrefs": [
"OMIM:612718"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome 3",
"xrefs": [
"DOID:0050712",
"MONDO:Lexical",
"OMIM:612718"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome type 3",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "creatine deficiency syndrome due to AGAT deficiency",
"xrefs": [
"OMIM:612718"
]
},
{
"pred": "hasExactSynonym",
"val": "disorder of glycine amidinotransferase activity",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "glycine amidinotransferase activity disease",
"xrefs": [
"MONDO:design_pattern"
]
}
],
"xrefs": [
{
"val": "DOID:0050712"
},
{
"val": "GARD:10323"
},
{
"val": "ICD9:270.8"
},
{
"val": "MEDGEN:436367"
},
{
"val": "MESH:C567192"
},
{
"val": "NANDO:1201033"
},
{
"val": "NANDO:2201299"
},
{
"val": "OMIM:612718"
},
{
"val": "Orphanet:35704"
},
{
"val": "SCTID:702440000"
},
{
"val": "UMLS:C2675179"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012996",
"name": "AGAT deficiency"
},
"entId": "MONDO:0012996",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012996",
"entType": "Disease",
"ldhId": "467873716",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873716",
"modified": "2025-10-07T15:44:52.543Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WyKK---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948257718300,
"agr": "HGNC:4175",
"alias_name": [
"L-arginine:glycine amidinotransferase"
],
"alias_symbol": [
"AGAT"
],
"ccds_id": [
"CCDS10122"
],
"date_approved_reserved": "1998-02-20",
"date_modified": "2020-04-02",
"date_name_changed": "2016-01-15",
"ena": [
"S68805"
],
"ensembl_gene_id": "ENSG00000171766",
"entrez_id": "2628",
"enzyme_id": [
"2.1.4.1"
],
"hgnc_id": "HGNC:4175",
"iuphar": "objectId:1246",
"location": "15q21.1",
"location_sortable": "15q21.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GATM"
],
"mane_select": [
"ENST00000396659.8",
"NM_001482.3"
],
"mgd_id": [
"MGI:1914342"
],
"name": "glycine amidinotransferase",
"omim_id": [
"602360"
],
"orphanet": 122037,
"pubmed_id": [
8313955
],
"refseq_accession": [
"NM_001482"
],
"rgd_id": [
"RGD:71090"
],
"status": "Approved",
"symbol": "GATM",
"ucsc_id": "uc001zvc.4",
"uniprot_ids": [
"P50440"
],
"uuid": "d059d691-6eea-4a17-86df-9e2eb45fd909",
"vega_id": "OTTHUMG00000131427"
}
},
"entId": "GATM",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4175",
"entType": "Gene",
"ldhId": "467827462",
"ldhIri": "https://genboree.org/cspec/Gene/id/467827462",
"modified": "2021-10-14T11:36:39.977Z",
"modifier": "genbadmin",
"rev": "_h6SHyqO--L"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "025_nuclear_GATM",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0012996",
"preferredTitle": "AGAT deficiency"
}
],
"gene": "GATM",
"preferredTranscript": "NM_001482.3"
}
],
"ns": "025",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243102",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243102",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--e"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CCDS",
"approval": {
"step1": {
"approvalDate": "2019-01-22T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-06-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-04-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-07-28T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cerebral Creatine Deficiency Syndromes",
"shortBaseName": "CCDS",
"shortTitle": "Cerebral Creatine Deficiency Syndromes VCEP",
"title": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50047",
"entIri": "http://clinicalgenome.org/affiliation/50047",
"entType": "Organization",
"ldhId": "639508884",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508884",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--L"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243095",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243095",
"modified": "2023-10-11T16:59:34.312Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykC--N"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:50:38.411Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for GAMT (guanidinoacetate methytransferase) Summary of ACMG-AMP Criteria for GAMT Variants",
"namespace": "GN026",
"releaseNotes": "* Added supporting strength for PM3 and PM4. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:50:38.411Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T18:00:36.255Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-13T19:23:33.152Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:55:19.342Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:12.780Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"026"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN026",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "026_PM6_nuclear_GAMT",
"additionalComments": "Assumed de novo but without confirmation of paternity and maternity.\nCCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with GAMT deficiency, to our knowledge. Furthermore, the observation that a variant in GAMT has arisen de novo does not support its causality because GAMT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GAMT, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "026",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243228",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243228",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--E"
},
{
"entContent": {
"_uniqueProp": "026_PM5_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "026",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243227",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243227",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--F"
},
{
"entContent": {
"_uniqueProp": "026_PS4_nuclear_GAMT",
"additionalComments": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\nCCDS VCEP notes for PS4:\nThis rule is typically used for autosomal dominant disorders, with PM3 used as a case-counting mechanism for autosomal recessive conditions.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "026",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243222",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243222",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--K"
},
{
"entContent": {
"_uniqueProp": "026_PS3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "026",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RT-PCR evidence of mis-splicing for non-canonical +1, +2, -2, -1 intronic variants with no evidence of normal splice products.** \n\nGAMT specifications: \nAny variant meeting the description for splicing assays below can meet PS3 or PS3\\_Supporting, and variants meeting the description for in vitro activity assays can meet PS3\\_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.\n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**\\<15% control activity when variant is expressed in GAMT-deficient fibroblasts or HeLa cells.** \n**\\* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.** \n\nGAMT specifications: \nAny variant meeting the description for splicing assays below can meet PS3 or PS3\\_Supporting, and variants meeting the description for in vitro activity assays can meet PS3\\_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.\n\n**In vitro expression** \nPS3\\_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts or HeLa cells and has \\<15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046. See [Appendix 2](https://docs.google.com/spreadsheets/d/1mjJRDMde-gPFVjnuP-Jbzr68GoaTr5pD/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) for further details on GAMT functional assays. \n\n**Splicing assays** \nFor non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing. \n\\* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells. \n\\* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3\\_Supporting. \n\\* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243221",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243221",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---D"
},
{
"entContent": {
"_uniqueProp": "026_PS2_nuclear_GAMT",
"additionalComments": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "026",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243220",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243220",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--K"
},
{
"entContent": {
"_uniqueProp": "026_BP6_nuclear_GAMT",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "026",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243244",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243244",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--B"
},
{
"entContent": {
"_uniqueProp": "026_BP5_nuclear_GAMT",
"additionalComments": "An individual could be a carrier of a pathogenic variant in GAMT and have another disorder.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "026",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243243",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243243",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--E"
},
{
"entContent": {
"_uniqueProp": "026_BP3_nuclear_GAMT",
"additionalComments": "There are no known repetitive regions without known function in GAMT.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "026",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243241",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243241",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--O"
},
{
"entContent": {
"_uniqueProp": "026_BP2_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "026",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in cis with a pathogenic variant (to take AR inheritance into account).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243240",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243240",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--F"
},
{
"entContent": {
"_uniqueProp": "026_PM4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "026",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Stop loss variants in GAMT have not been reported, as far as we are aware.\n\nGAMT specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": " Downgrade to PM4\\_Supporting for single amino acid deletions and insertions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243226",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243226",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--J"
},
{
"entContent": {
"_uniqueProp": "026_BP1_nuclear_GAMT",
"additionalComments": "Does not apply. All types of variants cause GAMT-D.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "026",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243239",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243239",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--H"
},
{
"entContent": {
"_uniqueProp": "026_BS2_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "026",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243236",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243236",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--J"
},
{
"entContent": {
"_uniqueProp": "026_BS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "026",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency >0.001 (0.1%) in gnomAD in any continental population in gnomAD with >2000 alleles. \n\nGAMT specifications:\n\n* Any variant with a frequency >0.001 (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD (max allelic contribution = 40%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243235",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243235",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--G"
},
{
"entContent": {
"_uniqueProp": "026_PM2_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "026",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Allele frequency \\<0.0004 (\\<0.04%) in all populations in gnomAD.**\n\nCCDS VCEP notes: It is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%.\n\nGAMT specifications:\n\n* All subpopulations in gnomAD must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2\\_Supporting (See Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.\n* If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243224",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243224",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--L"
},
{
"entContent": {
"_uniqueProp": "026_PS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "026",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is applicable as described.\n\nIf the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243219",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243219",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---C"
},
{
"entContent": {
"_uniqueProp": "026_BP7_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "026",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply this criterion as described.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243245",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243245",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--M"
},
{
"entContent": {
"_uniqueProp": "026_BS4_nuclear_GAMT",
"additionalComments": "Lack of segregation in a family. Caveat: The presence of phenocopies for common phenotypes.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "026",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243238",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243238",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--M"
},
{
"entContent": {
"_uniqueProp": "026_BA1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "026",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency >0.003 (0.3%) in gnomAD in any continental population in gnomAD with >2000 alleles.\n\nGAMT specifications:\n\n* Any variant with a frequency >0.003 (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD (max allelic contribution = 100%; max genetic contribution = 100%).\n* Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243234",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243234",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--C"
},
{
"entContent": {
"_uniqueProp": "026_PP4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "026",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4 points based on any combination of the following. Two or more data types are required to apply PP4\\_Strong: \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points) \n• GAMT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength. \n\\* For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 points based on any combination of the following. Two or more data types are recommended to apply PP4\\_Moderate: \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points) \n• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points) \n• GAMT enzyme activity \\<5% of normal (3 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-2 points based on: \n• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point) \n• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points)\n\n\\* Variant must meet PM2\\_Supporting for PP4 to apply at any strength",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243232",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243232",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--D"
},
{
"entContent": {
"_uniqueProp": "026_PP3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "026",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense changes, those with a REVEL score more than 0.75 will meet PP3.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)). Results must be consistent to apply this criterion.\n* For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.\n* Do not apply this rule for canonical splice site changes meeting PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243231",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243231",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--H"
},
{
"entContent": {
"_uniqueProp": "026_PP2_nuclear_GAMT",
"additionalComments": "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.\nCCDS VCEP notes for PP2: Does not apply; there are benign and pathogenic missense variants in GAMT",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "026",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243230",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243230",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--L"
},
{
"entContent": {
"_uniqueProp": "026_PP1_nuclear_GAMT",
"additionalComments": "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nCCDS VCEP notes for PP1: Sibships large enough to use meet this criterion are extremely rare. In addition, because GAMT is the only gene involved in GAMT-D, ALL patients are expected to be bi-allelic, regardless of whether the pathogenic variants can be, or have been, detected. A variant under assessment may not be the true pathogenic variant but instead in linkage disequilibrium with an unidentified pathogenic variant. For this reason, this criterion does not facilitate assessment of pathogenicity.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "026",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243229",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243229",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---B"
},
{
"entContent": {
"_uniqueProp": "026_PM3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "026",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Follow SVI guidance for PM3 ([https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf](https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf)).\n* Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243225",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243225",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--N"
},
{
"entContent": {
"_uniqueProp": "026_BP4_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "026",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense changes, REVEL score \\<0.5.\n* For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.\n* For non-canonical splice site variants, use SpliceAI ([https://spliceailookup.broadinstitute.org/](https://spliceailookup.broadinstitute.org/) ) and varSEAK ([https://varseak.bio/](https://varseak.bio/)) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores \\<0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243242",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243242",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--G"
},
{
"entContent": {
"_uniqueProp": "026_BS3_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "026",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\>30% normal GAA activity when the variant is expressed in a heterologous cell type. \nGAMT specifications: \nIn vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3\\_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243237",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243237",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--K"
},
{
"entContent": {
"_uniqueProp": "026_PP5_nuclear_GAMT",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "026",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243233",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243233",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--I"
},
{
"entContent": {
"_uniqueProp": "026_PM1_nuclear_GAMT",
"additionalComments": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "026",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243223",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243223",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--I"
},
{
"entContent": {
"_uniqueProp": "026_PVS1_nuclear_GAMT",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GAMT"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "026",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Nonsense-mediated decay predicted**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong or PVS1\\_Moderate will be applied, depending on whether >10% or \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**In frame loss of >10% of the protein.**\n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Strong will be applied if >10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \n\\* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Single exon or larger deletion resulting in loss of \\<10% of the protein.**\n\n**Initiator codon variant.** \n\nCCDS VCEP notes: \nLoss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).\n\n**Nonsense and frameshift variants** \n\\* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\\_Moderate will be applied if \\<10% of the protein is lost.\n\n**Splice site variants (+1, +2, -1, -2)** \n\\* All canonical splice site pairs in GAMT are GT-AG. \n\\* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \n\\* For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of \\<10% of the protein, apply PVS1\\_Moderate. \n\\* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \n\\* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.\n\n**Initiator codon variants** \n\\* To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur. \n\\* All initiator codon variants will meet PVS1\\_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP\\_000147.1).\n\n**Deletions (single or multi exon)** \n\\* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\\_Strong if >10% of the protein is predicted to be removed, and use PVS1\\_Moderate if \\<10% of the protein is predicted to be removed. \n\\* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\\_Strong if more than 10% of the protein is removed and PVS1\\_Moderate if \\<10% of the protein is removed. \n\\* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \n\\* [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions.\n\n**Duplications** \n\\* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243218",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243218",
"modified": "2022-09-14T20:50:38.849Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--J"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012999",
"lbl": "guanidinoacetate methyltransferase deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012999"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/cerebral_creatine_deficiency_syndrome_2"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/basis_in_disruption_of_process.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/disrupts_process.yaml"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/2578/guanidinoacetate-methyltransferase-deficiency"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1811642217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/154356"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C537622"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/124239003"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0574080"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050799"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_382"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/612736"
}
],
"definition": {
"val": "A creatine deficiency syndrome characterized by global developmental delay/intellectual disability (DD/ID), prominent speech delay, autistic/hyperactive behavioral disorders, seizures, and various types of pyramidal and/or extra-pyramidal manifestations.",
"xrefs": [
"Orphanet:382",
"https://orcid.org/0000-0001-5208-3432"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "GAMT deficiency",
"xrefs": [
"DOID:0050799",
"OMIM:612736",
"Orphanet:382"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome 2",
"xrefs": [
"DOID:0050799",
"MONDO:Lexical",
"OMIM:612736"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome type 2",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "disorder of guanidinoacetate N-methyltransferase activity",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/basis_in_disruption_of_process"
]
},
{
"pred": "hasExactSynonym",
"val": "guanidinoacetate N-methyltransferase activity disease",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "guanidinoacetate methyltransferase deficiency",
"xrefs": [
"DOID:0050799",
"OMIM:612736",
"Orphanet:382",
"icd11.foundation:1811642217"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CCDS2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "creatine deficiency syndrome due to GAMT deficiency"
}
],
"xrefs": [
{
"val": "DOID:0050799"
},
{
"val": "GARD:2578"
},
{
"val": "ICD9:277.6"
},
{
"val": "MEDGEN:154356"
},
{
"val": "MESH:C537622"
},
{
"val": "NANDO:1201034"
},
{
"val": "NANDO:2201300"
},
{
"val": "NORD:1967"
},
{
"val": "OMIM:612736"
},
{
"val": "Orphanet:382"
},
{
"val": "SCTID:124239003"
},
{
"val": "UMLS:C0574080"
},
{
"val": "icd11.foundation:1811642217"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012999",
"name": "guanidinoacetate methyltransferase deficiency"
},
"entId": "MONDO:0012999",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012999",
"entType": "Disease",
"ldhId": "467873663",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873663",
"modified": "2025-10-07T15:44:52.543Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WyK6---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948186415000,
"agr": "HGNC:4136",
"alias_symbol": [
"PIG2",
"TP53I2"
],
"ccds_id": [
"CCDS12064",
"CCDS45897"
],
"date_approved_reserved": "1996-07-19",
"date_modified": "2021-05-26",
"ena": [
"Z49878"
],
"ensembl_gene_id": "ENSG00000130005",
"entrez_id": "2593",
"gene_group": [
"7BS small molecule methyltransferases"
],
"gene_group_id": [
2063
],
"hgnc_id": "HGNC:4136",
"location": "19p13.3",
"location_sortable": "19p13.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GAMT"
],
"mane_select": [
"ENST00000252288.8",
"NM_000156.6"
],
"mgd_id": [
"MGI:1098221"
],
"name": "guanidinoacetate N-methyltransferase",
"omim_id": [
"601240"
],
"orphanet": 122011,
"pubmed_id": [
9570966,
8547310
],
"refseq_accession": [
"NM_138924"
],
"rgd_id": [
"RGD:2659"
],
"status": "Approved",
"symbol": "GAMT",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002lsj.5",
"uniprot_ids": [
"Q14353"
],
"uuid": "bd41090a-ab7b-4ce8-9e9c-94bd915309e5",
"vega_id": "OTTHUMG00000180095"
}
},
"entId": "GAMT",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4136",
"entType": "Gene",
"ldhId": "467827323",
"ldhIri": "https://genboree.org/cspec/Gene/id/467827323",
"modified": "2021-10-14T11:36:39.860Z",
"modifier": "genbadmin",
"rev": "_h6SHyqK--K"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "026_nuclear_GAMT",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0012999",
"preferredTitle": "guanidinoacetate methyltransferase deficiency"
}
],
"gene": "GAMT",
"preferredTranscript": "NM_000156.6"
}
],
"ns": "026",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PM3_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PM3",
"PM4",
"PM5",
"PP3_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243103",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243103",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--J"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CCDS",
"approval": {
"step1": {
"approvalDate": "2019-01-22T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-06-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-04-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-07-28T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cerebral Creatine Deficiency Syndromes",
"shortBaseName": "CCDS",
"shortTitle": "Cerebral Creatine Deficiency Syndromes VCEP",
"title": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50047",
"entIri": "http://clinicalgenome.org/affiliation/50047",
"entType": "Organization",
"ldhId": "639508884",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508884",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--L"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243096",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243096",
"modified": "2024-02-13T19:23:33.426Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykW--D"
},
{
"entContent": {
"approvedOn": "2022-09-14T20:51:04.353Z",
"description": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel ACMG Classification Rules Specified for Solute Carrier Family 6, Member 8 (SLC6A8; Creatine Transporter) Summary of ACMG-AMP Criteria for SLC6A8 Variants",
"namespace": "GN027",
"releaseNotes": "* Added PM6. This was previously approved by SVI for Version 1.0 but had not been included in the CSpec Registry.\n* Added clarification for PS2\\_Moderate.\n* Added clarification for points system for PP4, all previously approved by SVI.",
"releasedUnderRevision": true,
"shortTitle": "Cerebral Creatine Deficiency Syndromes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-09-14T20:51:04.353Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-10-11T18:15:28.297Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2022-09-07T17:53:39.002Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-07T17:51:40.093Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-09-12T21:25:00.425Z"
},
"name": "Approved For Release"
}
],
"tagNameSpaces": [
"027"
],
"title": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN027",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "027_BP7_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "027",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243273",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243273",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---E"
},
{
"entContent": {
"_uniqueProp": "027_BP2_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "027",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243268",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243268",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--G"
},
{
"entContent": {
"_uniqueProp": "027_PP5_nuclear_SLC6A8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "027",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243261",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243261",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---G"
},
{
"entContent": {
"_uniqueProp": "027_PP2_nuclear_SLC6A8",
"additionalComments": "Not applicable, gnomAD (01/2019) expected missense 243.5, observed missense 117, for Z=2.94 (o/e =0.48). No constraint against missense variation.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "027",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243258",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243258",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--Q"
},
{
"entContent": {
"_uniqueProp": "027_PP1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP1",
"ns": "027",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* 3 affected segregations + 0 unaffected segregations OR\n* 2 affected segregations + 3 unaffected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* 2 affected segregations + 0 unaffected segregations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* 1 affected family member + 3 unaffected segregations.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243257",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243257",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--R"
},
{
"entContent": {
"_uniqueProp": "027_BP5_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "027",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\nBP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243271",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243271",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--I"
},
{
"entContent": {
"_uniqueProp": "027_BP3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "027",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243269",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243269",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---F"
},
{
"entContent": {
"_uniqueProp": "027_BS1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS1",
"ns": "027",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243263",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243263",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--H"
},
{
"entContent": {
"_uniqueProp": "027_PP3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "027",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* REVEL score >0.75 for missense variants\n* In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.\n* Predicted impact on splicing by SpliceAI and varSEAK.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243259",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243259",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpO--A"
},
{
"entContent": {
"_uniqueProp": "027_PM1_nuclear_SLC6A8",
"additionalComments": "Not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "027",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243251",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243251",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--L"
},
{
"entContent": {
"_uniqueProp": "027_PS3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "027",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RT-PCR evidence of mis-splicing for non-canonical intronic variants.**\n\nFor non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts\n* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.\nFor non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243249",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243249",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxoy---"
},
{
"entContent": {
"_uniqueProp": "027_PS2_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "027",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.\n\nX-linked disorder. Only maternity needs to be confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243248",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243248",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpO--_"
},
{
"entContent": {
"_uniqueProp": "027_PS1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "027",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "PS1 is applicable as described.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243247",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243247",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--Q"
},
{
"entContent": {
"_uniqueProp": "027_PM3_nuclear_SLC6A8",
"additionalComments": "SLC6A8 is an X-linked gene, therefore PM3 is not applicable",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "027",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243253",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243253",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---J"
},
{
"entContent": {
"_uniqueProp": "027_PS4_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS4",
"ns": "027",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* 4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* 3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* 2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.\n* Variant must meet PM2_Supporting criterion for PS4 to apply.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* One independent male proband in addition to any proband used for PP4.\n* Variant must meet PM2\\_Supporting criterion for PS4 to apply.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243250",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243250",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---I"
},
{
"entContent": {
"_uniqueProp": "027_PVS1_nuclear_SLC6A8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PVS1",
"ns": "027",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "* Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.\n* Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243246",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243246",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo6---"
},
{
"entContent": {
"_uniqueProp": "027_BP1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "027",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243267",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243267",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpO---"
},
{
"entContent": {
"_uniqueProp": "027_BS2_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "027",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the homozygous state in a healthy adult",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243264",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243264",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--O"
},
{
"entContent": {
"_uniqueProp": "027_BA1_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BA1",
"ns": "027",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243262",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243262",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--U"
},
{
"entContent": {
"_uniqueProp": "027_PM6_nuclear_SLC6A8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "027",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243256",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243256",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--S"
},
{
"entContent": {
"_uniqueProp": "027_PM5_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "027",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243255",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243255",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--P"
},
{
"entContent": {
"_uniqueProp": "027_BP6_nuclear_SLC6A8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "027",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243272",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243272",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpK--L"
},
{
"entContent": {
"_uniqueProp": "027_BP4_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "027",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* REVEL score <0.2 for missense variants\n* In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.\n* No predicted impact on splicing by SpliceAI and varSEAK.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243270",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243270",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--P"
},
{
"entContent": {
"_uniqueProp": "027_BS4_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "027",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243266",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243266",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxo2--N"
},
{
"entContent": {
"_uniqueProp": "027_BS3_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "027",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).\n* RT-PCR evidence demonstrating no observable effect of splicing.\n* Expression assay demonstrating wild type transcript levels",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243265",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243265",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--J"
},
{
"entContent": {
"_uniqueProp": "027_PP4_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "027",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4 or more points based on combinations of the following. \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are required for PP4\\_Strong.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.\n* For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "3 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n* Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)\n* Deficient creatine uptake in cultured fibroblasts (\\<10% of normal with \\<125uM creatine) (3 points)\n\nAdditional specifications:\n\n* Two or more data types are recommended for PP4\\_Moderate.\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-2 or more points based on: \n\n* Elevated urine creatine/creatinine ratio on one occasion (1 point)\n* Elevated urine creatine/creatinine ratio on more than one occasion (2 points)\n\nAdditional specifications:\n\n* An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.\n* Variant must meet PM2\\_Supporting for PP4 to apply at any strength.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243260",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243260",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxpS--K"
},
{
"entContent": {
"_uniqueProp": "027_PM4_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "027",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243254",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243254",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxou--T"
},
{
"entContent": {
"_uniqueProp": "027_PM2_nuclear_SLC6A8",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SLC6A8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM2",
"ns": "027",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: \\<0.00002 (0.002%) AND 0 hemizygotes in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "643243252",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/643243252",
"modified": "2022-09-14T20:51:04.826Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHxp---H"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010305",
"lbl": "creatine transporter deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010305"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/cerebral_creatine_deficiency_syndrome_1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/337451"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535598"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/698290008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1845862"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050800"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C125665"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_52503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/300352"
}
],
"definition": {
"val": "X-linked creatine transporter deficiency (CRTR-D) is a creatine deficiency syndrome characterized clinically by global developmental delay/ intellectual disability (DD/ID) with prominent speech/language delay, autistic behavior and seizures.",
"xrefs": [
"Orphanet:52503"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "SLC6A8 deficiency",
"xrefs": [
"DOID:0050800",
"Orphanet:52503"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome 1",
"xrefs": [
"DOID:0050800",
"MONDO:Lexical",
"NCIT:C125665",
"OMIM:300352"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome 1, X-linked recessive"
},
{
"pred": "hasExactSynonym",
"val": "cerebral creatine deficiency syndrome type 1",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "creatine transporter deficiency",
"xrefs": [
"DOID:0050800",
"Orphanet:52503"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CCDS1",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "X-linked creatine deficiency",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"val": "X-linked creatine deficiency syndrome",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"val": "X-linked creatine transporter deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "creatine deficiency syndrome, X-linked"
},
{
"pred": "hasRelatedSynonym",
"val": "creatine deficiency, X-linked",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"val": "creatine transporter defect"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked with seizures, short stature and midface hypoplasia",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked, with creatine Transport deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked, with creatine transport deficiency",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked, with seizures, short stature, and midface hypoplasia"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked with seizures, short stature and midface hypoplasia",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked, with creatine Transport deficiency"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked, with creatine transport deficiency",
"xrefs": [
"GARD:0001608"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked, with seizures, short stature, and midface hypoplasia"
}
],
"xrefs": [
{
"val": "DOID:0050800"
},
{
"val": "GARD:1608"
},
{
"val": "ICD9:758.81"
},
{
"val": "MEDGEN:337451"
},
{
"val": "MESH:C535598"
},
{
"val": "NANDO:1201035"
},
{
"val": "NANDO:2201301"
},
{
"val": "NCIT:C125665"
},
{
"val": "NORD:1966"
},
{
"val": "OMIM:300352"
},
{
"val": "Orphanet:52503"
},
{
"val": "SCTID:698290008"
},
{
"val": "UMLS:C1845862"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010305",
"name": "creatine transporter deficiency"
},
"entId": "MONDO:0010305",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010305",
"entType": "Disease",
"ldhId": "467873958",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873958",
"modified": "2025-10-07T15:44:10.550Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WIzu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963013279700,
"agr": "HGNC:11055",
"alias_name": [
"creatine transporter"
],
"alias_symbol": [
"CRTR",
"CT1"
],
"bioparadigms_slc": "SLC6A8",
"ccds_id": [
"CCDS14726",
"CCDS48190"
],
"date_approved_reserved": "1994-12-19",
"date_modified": "2020-04-02",
"date_name_changed": "2016-02-17",
"ensembl_gene_id": "ENSG00000130821",
"entrez_id": "6535",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:11055",
"iuphar": "objectId:934",
"location": "Xq28",
"location_sortable": "Xq28",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SLC6A8",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SLC6A8"
],
"mane_select": [
"ENST00000253122.10",
"NM_005629.4"
],
"mgd_id": [
"MGI:2147834"
],
"name": "solute carrier family 6 member 8",
"omim_id": [
"300036"
],
"orphanet": 119705,
"prev_name": [
"solute carrier family 6 (neurotransmitter transporter, creatine), member 8",
"solute carrier family 6 (neurotransmitter transporter), member 8"
],
"pubmed_id": [
7774949
],
"refseq_accession": [
"NM_001142805"
],
"rgd_id": [
"RGD:619711"
],
"status": "Approved",
"symbol": "SLC6A8",
"ucsc_id": "uc004fib.4",
"uniprot_ids": [
"P48029"
],
"uuid": "2ce602d6-c21c-4d62-9e3f-d2bf5dcf4e25",
"vega_id": "OTTHUMG00000024208"
}
},
"entId": "SLC6A8",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11055",
"entType": "Gene",
"ldhId": "467856291",
"ldhIri": "https://genboree.org/cspec/Gene/id/467856291",
"modified": "2021-10-14T11:37:07.969Z",
"modifier": "genbadmin",
"rev": "_h6SHz8i--n"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "027_nuclear_SLC6A8",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0010305",
"preferredTitle": "creatine transporter deficiency"
}
],
"gene": "SLC6A8",
"preferredTranscript": "NM_005629.4"
}
],
"ns": "027",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243104",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243104",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--d"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CCDS",
"approval": {
"step1": {
"approvalDate": "2019-01-22T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-06-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-04-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-07-28T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cerebral Creatine Deficiency Syndromes",
"shortBaseName": "CCDS",
"shortTitle": "Cerebral Creatine Deficiency Syndromes VCEP",
"title": "Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50047",
"entIri": "http://clinicalgenome.org/affiliation/50047",
"entType": "Organization",
"ldhId": "639508884",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508884",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--L"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243097",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243097",
"modified": "2023-10-11T18:15:28.510Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHyk---G"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN028",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:11:58.490Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"028"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for POLG Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN028",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0044970",
"lbl": "mitochondrial disease",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0044970"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/specific_disease_by_dysfunctional_structure.yaml"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://www.epilepsydiagnosis.org/aetiology/metabolic-groupoverview.html#mitochondrial"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/155901"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0751651"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#harrisons_view",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare_grouping"
],
"xrefs": [
{
"val": "MEDGEN:155901"
},
{
"val": "NANDO:1200173"
},
{
"val": "NANDO:2100163"
},
{
"val": "UMLS:C0751651"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0044970",
"name": "mitochondrial disease"
},
"entId": "MONDO:0044970",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0044970",
"entType": "Disease",
"ldhId": "135642194",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642194",
"modified": "2025-10-07T15:48:22.065Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7a-qO---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056957870014500,
"agr": "HGNC:9179",
"alias_symbol": [
"POLG1",
"POLGA"
],
"ccds_id": [
"CCDS10350"
],
"curator_notes": [
"[Khan et al](https://www.ncbi.nlm.nih.gov/pubmed/32138667) reports that this complex locus also contains a second alternate reading frame"
],
"date_approved_reserved": "1992-02-06",
"date_modified": "2021-04-13",
"date_name_changed": "2016-07-11",
"ena": [
"X98093"
],
"ensembl_gene_id": "ENSG00000140521",
"entrez_id": "5428",
"gene_group": [
"DNA polymerases",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
535,
1691
],
"hgnc_id": "HGNC:9179",
"location": "15q26.1",
"location_sortable": "15q26.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_765|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_765.xml"
],
"mane_select": [
"ENST00000268124.11",
"NM_002693.3"
],
"mgd_id": [
"MGI:1196389"
],
"name": "DNA polymerase gamma, catalytic subunit",
"omim_id": [
"174763"
],
"orphanet": 117925,
"prev_name": [
"polymerase (DNA directed), gamma",
"polymerase (DNA) gamma, catalytic subunit"
],
"pubmed_id": [
9465903,
32138667
],
"refseq_accession": [
"NM_002693"
],
"rgd_id": [
"RGD:620057"
],
"status": "Approved",
"symbol": "POLG",
"ucsc_id": "uc002bns.5",
"uniprot_ids": [
"P54098"
],
"uuid": "3d221088-ac02-4bc9-98bf-3f9d97e8d9c9",
"vega_id": "OTTHUMG00000149646"
},
"NCBI": {
"id": "5428"
}
},
"entId": "POLG",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9179",
"entType": "Gene",
"ldhId": "135641934",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641934",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "028_nuclear_POLG",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0044970",
"preferredTitle": "Mitochondrial disease"
}
],
"gene": "POLG",
"preferredTranscript": "NM_002693.2"
}
],
"ns": "028",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243105",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243105",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--U"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243098",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243098",
"modified": "2022-08-18T19:12:02.919Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--_"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN029",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:03.420Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"029"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ETHE1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN029",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011229",
"lbl": "ethylmalonic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5671"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/encephalopathy_ethylmalonic"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/2198/ethylmalonic-encephalopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1966714550"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/355966"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535737"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/723307008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1865349"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060640"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_51188"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/602473"
}
],
"definition": {
"val": "Ethylmalonic acid encephalopathy (EE) is defined by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.",
"xrefs": [
"Orphanet:51188"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "EE",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "EPEMA syndrome",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "eme",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, ethylmalonic",
"xrefs": [
"GARD:0002198",
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, petechiae, and ethylmalonic aciduria",
"xrefs": [
"GARD:0002198"
]
},
{
"pred": "hasRelatedSynonym",
"val": "syndrome of encephalopathy, petechiae, and ethylmalonic aciduria",
"xrefs": [
"GARD:0002198"
]
}
],
"xrefs": [
{
"val": "DOID:0060640"
},
{
"val": "GARD:2198"
},
{
"val": "MEDGEN:355966"
},
{
"val": "MESH:C535737"
},
{
"val": "OMIM:602473"
},
{
"val": "Orphanet:51188"
},
{
"val": "SCTID:723307008"
},
{
"val": "UMLS:C1865349"
},
{
"val": "icd11.foundation:1966714550"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011229",
"name": "ethylmalonic encephalopathy"
},
"entId": "MONDO:0011229",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011229",
"entType": "Disease",
"ldhId": "135642196",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642196",
"modified": "2025-10-07T15:44:25.227Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WXOy---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056947152519200,
"agr": "HGNC:23287",
"alias_symbol": [
"YF13H12",
"HSCO"
],
"ccds_id": [
"CCDS12622"
],
"date_approved_reserved": "2003-12-15",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ensembl_gene_id": "ENSG00000105755",
"entrez_id": "23474",
"enzyme_id": [
"1.13.11.18"
],
"hgnc_id": "HGNC:23287",
"location": "19q13.31",
"location_sortable": "19q13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000292147.7",
"NM_014297.5"
],
"mgd_id": [
"MGI:1913321"
],
"name": "ETHE1 persulfide dioxygenase",
"omim_id": [
"608451"
],
"orphanet": 121629,
"prev_name": [
"ethylmalonic encephalopathy 1"
],
"pubmed_id": [
19136963
],
"refseq_accession": [
"NM_014297"
],
"rgd_id": [
"RGD:1311034"
],
"status": "Approved",
"symbol": "ETHE1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002owp.3",
"uniprot_ids": [
"O95571"
],
"uuid": "636414c2-a027-4641-9152-9eda9a4a0faa",
"vega_id": "OTTHUMG00000182697"
},
"NCBI": {
"id": "23474"
}
},
"entId": "ETHE1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:23287",
"entType": "Gene",
"ldhId": "135641936",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641936",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "029_nuclear_ETHE1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0011229",
"preferredTitle": "Ethylmalonic encephalopathy"
}
],
"gene": "ETHE1",
"preferredTranscript": "NM_014297.5"
}
],
"ns": "029",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243106",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243106",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--M"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243099",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243099",
"modified": "2022-08-18T19:12:07.364Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju---"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN030",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:07.840Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"030"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC19A3 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN030",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011841",
"lbl": "biotin-responsive basal ganglia disease",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4205"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/basal_ganglia_disease_biotin_thiamine_responsive"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005527"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1776831202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/375289"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C537658"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/703522009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/723557004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1843807"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050659"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199348"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_65284"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/607483"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BBGD",
"xrefs": [
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BTBGD",
"xrefs": [
"OMIM:607483",
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"val": "biotin-thiamine-responsive basal ganglia disease",
"xrefs": [
"Orphanet:65284"
]
},
{
"pred": "hasExactSynonym",
"val": "thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2)"
},
{
"pred": "hasExactSynonym",
"val": "thiamine-responsive encephalopathy",
"xrefs": [
"MONDO:0016050",
"Orphanet:199348"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "THMD2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "basal ganglia disease, biotin-responsive"
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, thiamine-responsive"
},
{
"pred": "hasRelatedSynonym",
"val": "thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive type)",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0050659"
},
{
"val": "GARD:10237"
},
{
"val": "ICD9:333.99"
},
{
"val": "MEDGEN:375289"
},
{
"val": "MESH:C537658"
},
{
"val": "OMIM:607483"
},
{
"val": "Orphanet:199348"
},
{
"val": "Orphanet:65284"
},
{
"val": "SCTID:703522009"
},
{
"val": "SCTID:723557004"
},
{
"val": "UMLS:C1843807"
},
{
"val": "icd11.foundation:1776831202"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011841",
"name": "biotin-responsive basal ganglia disease"
},
"entId": "MONDO:0011841",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011841",
"entType": "Disease",
"ldhId": "135642197",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642197",
"modified": "2025-10-07T15:44:35.158Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wh-W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963120234500,
"agr": "HGNC:16266",
"alias_name": [
"thiamine transporter 2"
],
"alias_symbol": [
"THTR2"
],
"bioparadigms_slc": "SLC19A3",
"ccds_id": [
"CCDS2468"
],
"date_approved_reserved": "2001-07-19",
"date_modified": "2017-04-20",
"date_name_changed": "2016-02-17",
"ena": [
"AF271633"
],
"ensembl_gene_id": "ENSG00000135917",
"entrez_id": "80704",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:16266",
"iuphar": "objectId:1016",
"location": "2q36.3",
"location_sortable": "02q36.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000644224.2",
"NM_025243.4"
],
"mgd_id": [
"MGI:1931307"
],
"name": "solute carrier family 19 member 3",
"omim_id": [
"606152"
],
"orphanet": 118766,
"prev_name": [
"solute carrier family 19, member 3",
"solute carrier family 19 (thiamine transporter), member 3"
],
"pubmed_id": [
11136550,
15871139
],
"refseq_accession": [
"NM_025243"
],
"rgd_id": [
"RGD:1311413"
],
"status": "Approved",
"symbol": "SLC19A3",
"ucsc_id": "uc002vpi.4",
"uniprot_ids": [
"Q9BZV2"
],
"uuid": "560fc138-355e-419a-9050-d523d75f502b",
"vega_id": "OTTHUMG00000133185"
},
"NCBI": {
"id": "80704"
}
},
"entId": "SLC19A3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:16266",
"entType": "Gene",
"ldhId": "135641937",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641937",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "030_nuclear_SLC19A3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0011841",
"preferredTitle": "Biotin-responsive basal ganglia disease"
}
],
"gene": "SLC19A3",
"preferredTranscript": "NM_025243.4"
}
],
"ns": "030",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243107",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243107",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--i"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243100",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243100",
"modified": "2022-08-18T19:12:11.423Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--_"
},
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN031",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:11.889Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"031"
],
"title": "ClinGen Mitochondrial Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PDHA1 Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN031",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019169",
"lbl": "pyruvate dehydrogenase deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100033"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/specific_disease_by_dysfunctional_structure.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1124597954"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/19610"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/46683007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0034345"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3649"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C103968"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_765"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS312170"
}
],
"definition": {
"val": "A rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency.",
"xrefs": [
"Orphanet:765"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDH",
"xrefs": [
"NCIT:C103968",
"Orphanet:765"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDHC",
"xrefs": [
"Orphanet:765"
]
},
{
"pred": "hasExactSynonym",
"val": "Pyruvate Dehydrogenase Complex Deficiency",
"xrefs": [
"NORD:1641",
"OMIMPS:312170",
"Orphanet:765",
"icd11.foundation:1124597954"
]
},
{
"pred": "hasExactSynonym",
"val": "deficiency of pyruvic dehydrogenase",
"xrefs": [
"DOID:3649"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate decarboxylase deficiency",
"xrefs": [
"DOID:3649",
"MONDO:0005934"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase complex deficiency",
"xrefs": [
"OMIMPS:312170",
"Orphanet:765",
"icd11.foundation:1124597954"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase complex deficiency disease",
"xrefs": [
"DOID:3649"
]
},
{
"pred": "hasExactSynonym",
"val": "pyruvate dehydrogenase deficiency",
"xrefs": [
"DOID:3649",
"NCIT:C103968",
"Orphanet:765",
"icd11.foundation:1124597954"
]
}
],
"xrefs": [
{
"val": "DOID:3649"
},
{
"val": "GARD:7513"
},
{
"val": "ICD9:277.89"
},
{
"val": "MEDGEN:19610"
},
{
"val": "NANDO:2200518"
},
{
"val": "NCIT:C103968"
},
{
"val": "NORD:1641"
},
{
"val": "OMIMPS:312170"
},
{
"val": "Orphanet:765"
},
{
"val": "SCTID:46683007"
},
{
"val": "UMLS:C0034345"
},
{
"val": "icd11.foundation:1124597954"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019169",
"name": "pyruvate dehydrogenase deficiency"
},
"entId": "MONDO:0019169",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019169",
"entType": "Disease",
"ldhId": "135642195",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642195",
"modified": "2025-10-07T15:46:39.824Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Ya3e---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056957250306000,
"agr": "HGNC:8806",
"alias_name": [
"pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial"
],
"ccds_id": [
"CCDS14192",
"CCDS55382",
"CCDS55381",
"CCDS55380"
],
"date_approved_reserved": "1989-06-30",
"date_modified": "2020-04-02",
"date_name_changed": "2019-11-26",
"ensembl_gene_id": "ENSG00000131828",
"entrez_id": "5160",
"enzyme_id": [
"1.2.4.1"
],
"gene_group": [
"Pyruvate dehydrogenase complex"
],
"gene_group_id": [
1547
],
"hgnc_id": "HGNC:8806",
"location": "Xp22.12",
"location_sortable": "Xp22.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/PDHA1"
],
"mane_select": [
"ENST00000422285.7",
"NM_000284.4"
],
"mgd_id": [
"MGI:97532"
],
"name": "pyruvate dehydrogenase E1 subunit alpha 1",
"omim_id": [
"300502"
],
"orphanet": 124161,
"prev_name": [
"pyruvate dehydrogenase (lipoamide) alpha 1",
"pyruvate dehydrogenase alpha 1"
],
"prev_symbol": [
"PDHA"
],
"refseq_accession": [
"NM_000284"
],
"rgd_id": [
"RGD:3286"
],
"status": "Approved",
"symbol": "PDHA1",
"ucsc_id": "uc011mjc.3",
"uniprot_ids": [
"P08559"
],
"uuid": "49150386-c42a-4826-bf0d-e7cb29bd23fd",
"vega_id": "OTTHUMG00000021224"
},
"NCBI": {
"id": "5160"
}
},
"entId": "PDHA1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8806",
"entType": "Gene",
"ldhId": "135641935",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641935",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "031_nuclear_PDHA1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0019169",
"preferredTitle": "Pyruvate dehydrogenase deficiency"
}
],
"gene": "PDHA1",
"preferredTranscript": "NM_000284.4"
}
],
"ns": "031",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243108",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243108",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--_"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2020-05-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Mitochondrial Diseases",
"shortBaseName": "Mito Disease",
"shortTitle": "Mitochondrial Diseases VCEP",
"title": "Mitochondrial Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50027",
"entIri": "http://clinicalgenome.org/affiliation/50027",
"entType": "Organization",
"ldhId": "135637647",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637647",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--W"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2020-04-30T00:00:00.000Z",
"description": "This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN014",
"shortTitle": "Mitochondrial Disease Nuclear and Mitochondrial Variant Interpretation Guidelines ntDNA",
"specificationSource": "https://www.clinicalgenome.org/affiliation/50027/docs/assertion-criteria",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2020-04-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"014"
],
"title": "ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA",
"version": "1.0.0"
},
"entId": "GN014",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637587",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637587",
"modified": "2023-09-29T15:16:47.661Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--M"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243101",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243101",
"modified": "2022-08-18T19:12:15.742Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6---"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:22:58.500Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN032",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:17.106Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:24:55.246Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:16:57.373Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:28.132Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:22:58.500Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"032"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN032",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "032_BP7_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "032",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176865",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176865",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--F"
},
{
"entContent": {
"_uniqueProp": "032_PP5_nuclear_TCF4",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "032",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176864",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176864",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--E"
},
{
"entContent": {
"_uniqueProp": "032_BS4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "032",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families\n* Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176853",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176853",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--C"
},
{
"entContent": {
"_uniqueProp": "032_BP1_nuclear_TCF4",
"additionalComments": "Not applicable for TCF4.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "032",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176852",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176852",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--G"
},
{
"entContent": {
"_uniqueProp": "032_PM1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "032",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Basic Helix-Loop-Helix domain (bHLH): aa 564-617[3](#PMID_17436254),[2](#PMID_22045651)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176843",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176843",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--A"
},
{
"entContent": {
"_uniqueProp": "032_BS3_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "032",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176841",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176841",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpO--C"
},
{
"entContent": {
"_uniqueProp": "032_BS2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "032",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176840",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176840",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--A"
},
{
"entContent": {
"_uniqueProp": "032_PM2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "032",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176838",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176838",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--A"
},
{
"entContent": {
"_uniqueProp": "032_BP6_nuclear_TCF4",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "032",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176863",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176863",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--D"
},
{
"entContent": {
"_uniqueProp": "032_PP1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "032",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176860",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176860",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxo6--B"
},
{
"entContent": {
"_uniqueProp": "032_BP4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "032",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176859",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176859",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--G"
},
{
"entContent": {
"_uniqueProp": "032_BA1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "032",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176848",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176848",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--E"
},
{
"entContent": {
"_uniqueProp": "032_PS4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar). However, the independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "032",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176846",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176846",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--D"
},
{
"entContent": {
"_uniqueProp": "032_PS3_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "032",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176858",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176858",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxo6--A"
},
{
"entContent": {
"_uniqueProp": "032_BP2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _TCF4_ results in embryonic lethality/drastic pheotype.[4](#PMID_17878293)",
"label": "BP2",
"ns": "032",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* Applicable for _TCF4_ for _in trans_ state",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176856",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176856",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--F"
},
{
"entContent": {
"_uniqueProp": "032_PM6_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* Evidence from literature must be fully evaluated to support independent events.\n* Because of the very high de novo rate of pathogenic variants in _TCF4_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "032",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176854",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176854",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--D"
},
{
"entContent": {
"_uniqueProp": "032_PP3_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "032",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Clarification"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176845",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176845",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--C"
},
{
"entContent": {
"_uniqueProp": "032_BP5_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _TCF4_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "032",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176862",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176862",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpO--F"
},
{
"entContent": {
"_uniqueProp": "032_PVS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "For intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for TCF4, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "032",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E643 which corresponds to the distal most de novo truncating variant in an affected patient reported to date.[1](#PMID_29695756)\n* PVS1 can be applied for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _TCF4._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176861",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176861",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--H"
},
{
"entContent": {
"_uniqueProp": "032_BP3_nuclear_TCF4",
"additionalComments": "Not applicable for TCF4.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "032",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176857",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176857",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--C"
},
{
"entContent": {
"_uniqueProp": "032_PS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "032",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176855",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176855",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--E"
},
{
"entContent": {
"_uniqueProp": "032_BS1_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles \\[assumes 50/50 male/female ratio\\]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "032",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease.\n\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176850",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176850",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpC--B"
},
{
"entContent": {
"_uniqueProp": "032_PM5_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "032",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176842",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176842",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpO--D"
},
{
"entContent": {
"_uniqueProp": "032_PP4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "032",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176839",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176839",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--_"
},
{
"entContent": {
"_uniqueProp": "032_PM4_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "032",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176851",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176851",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--F"
},
{
"entContent": {
"_uniqueProp": "032_PM3_nuclear_TCF4",
"additionalComments": "Not applicable for TCF4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "032",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176849",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176849",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpO--E"
},
{
"entContent": {
"_uniqueProp": "032_PS2_nuclear_TCF4",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in TCF4, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "032",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176847",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176847",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxpW--B"
},
{
"entContent": {
"_uniqueProp": "032_PP2_nuclear_TCF4",
"additionalComments": "Not applicable for TCF4.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"TCF4"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "032",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572176844",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572176844",
"modified": "2023-05-09T17:22:59.253Z",
"modifier": "arossel",
"rev": "_h6SHxoy--B"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012589",
"lbl": "Pitt-Hopkins syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012589"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/pitt_hopkins_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/4372/pitt-hopkins-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/2040786134"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/370910"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C537403"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702344008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1970431"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060488"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129872"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_2896"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/610954"
}
],
"definition": {
"val": "Pitt-Hopkins syndrome (PHS) is characterized by the association of intellectual deficit, characteristic facial dysmorphism and problems of abnormal and irregular breathing.",
"xrefs": [
"Orphanet:2896"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Pitt-Hopkins syndrome",
"xrefs": [
"DOID:0060488",
"MONDO:Lexical",
"NCIT:C129872",
"OMIM:610954",
"Orphanet:2896",
"icd11.foundation:2040786134"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PTHS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Pitt Hopkins syndrome",
"xrefs": [
"GARD:0004372"
]
},
{
"pred": "hasRelatedSynonym",
"val": "encephalopathy, Severe epileptic, with autonomic dysfunction"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, Syndromal, with intermittent hyperventilation"
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea",
"xrefs": [
"GARD:0004372"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, Syndromal, with intermittent hyperventilation"
}
],
"xrefs": [
{
"val": "DOID:0060488"
},
{
"val": "GARD:4372"
},
{
"val": "ICD9:758.5"
},
{
"val": "MEDGEN:370910"
},
{
"val": "MESH:C537403"
},
{
"val": "NCIT:C129872"
},
{
"val": "NORD:1921"
},
{
"val": "OMIM:610954"
},
{
"val": "Orphanet:2896"
},
{
"val": "SCTID:702344008"
},
{
"val": "UMLS:C1970431"
},
{
"val": "icd11.foundation:2040786134"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012589",
"name": "Pitt-Hopkins syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0012589",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012589",
"entType": "Disease",
"ldhId": "135642214",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642214",
"modified": "2025-10-07T15:44:46.251Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Ws_G---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056964794810400,
"agr": "HGNC:11634",
"alias_name": [
"SL3-3 enhancer factor 2",
"class B basic helix-loop-helix protein 19",
"immunoglobulin transcription factor 2"
],
"alias_symbol": [
"SEF2-1B",
"ITF2",
"bHLHb19",
"E2-2"
],
"ccds_id": [
"CCDS86672",
"CCDS77192",
"CCDS42438",
"CCDS58623",
"CCDS58624",
"CCDS58625",
"CCDS58626",
"CCDS58627",
"CCDS58628",
"CCDS82257",
"CCDS82255",
"CCDS77191",
"CCDS58629",
"CCDS58630",
"CCDS58631",
"CCDS59321",
"CCDS11960",
"CCDS86671"
],
"date_approved_reserved": "1990-10-16",
"date_modified": "2020-04-02",
"ena": [
"M74719"
],
"ensembl_gene_id": "ENSG00000196628",
"entrez_id": "6925",
"gene_group": [
"Basic helix-loop-helix proteins"
],
"gene_group_id": [
420
],
"hgnc_id": "HGNC:11634",
"location": "18q21.2",
"location_sortable": "18q21.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/TCF4"
],
"mane_select": [
"ENST00000354452.8",
"NM_001083962.2"
],
"mgd_id": [
"MGI:98506"
],
"name": "transcription factor 4",
"omim_id": [
"602272"
],
"orphanet": 158595,
"pubmed_id": [
9302263,
2308860
],
"refseq_accession": [
"NM_003199"
],
"rgd_id": [
"RGD:69271"
],
"status": "Approved",
"symbol": "TCF4",
"ucsc_id": "uc002lfz.3",
"uniprot_ids": [
"P15884"
],
"uuid": "31116aa1-aa61-42da-bb3d-7f6f2325744d",
"vega_id": "OTTHUMG00000132713"
},
"NCBI": {
"id": "6925"
}
},
"entId": "TCF4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11634",
"entType": "Gene",
"ldhId": "135641942",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641942",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "032_nuclear_TCF4",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0012589",
"preferredTitle": "Pitt-Hopkins syndrome"
}
],
"gene": "TCF4",
"preferredTranscript": "NM_001083962.1"
}
],
"ns": "032",
"references": [
{
"auths": [
"Mary L",
"Piton A",
"et al."
],
"doiStr": "10.1038/s41431-018-0096-4",
"id": "29695756",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 996-1006.",
"source": "Eur J Hum Genet",
"title": "Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis.",
"vol": "26",
"year": "2018"
},
{
"auths": [
"Whalen S",
"Héron D",
"et al."
],
"doiStr": "10.1002/humu.21639",
"id": "22045651",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 64-72.",
"source": "Hum Mutat",
"title": "Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.",
"vol": "33",
"year": "2012"
},
{
"auths": [
"Amiel J",
"Rio M",
"et al."
],
"doiStr": "10.1086/515582",
"id": "17436254",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 988-93.",
"source": "Am J Hum Genet",
"title": "Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.",
"vol": "80",
"year": "2007"
},
{
"auths": [
"Flora A",
"Garcia JJ",
"et al."
],
"doiStr": "10.1073/pnas.0707456104",
"id": "17878293",
"iss": "(39)",
"namespace": "pmid",
"pages": "p. 15382-7.",
"source": "Proc Natl Acad Sci U S A",
"title": "The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors.",
"vol": "104",
"year": "2007"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule13, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243109",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243109",
"modified": "2023-05-09T17:22:59.160Z",
"modifier": "arossel",
"rev": "_h6SHyTS--Y"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243102",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243102",
"modified": "2023-09-29T15:16:49.280Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--V"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:23:41.958Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN033",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:21.126Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:04.208Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:35.379Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:44.472Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:23:41.958Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"033"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN033",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "033_BP5_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _SLC9A6_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* The variant should be in the hemizygous state in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "033",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178241",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178241",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--P"
},
{
"entContent": {
"_uniqueProp": "033_BS4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "033",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178232",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178232",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--H"
},
{
"entContent": {
"_uniqueProp": "033_BP1_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "033",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178231",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178231",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpC--H"
},
{
"entContent": {
"_uniqueProp": "033_PM5_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "033",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178221",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178221",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--I"
},
{
"entContent": {
"_uniqueProp": "033_BS3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "033",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178220",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178220",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--D"
},
{
"entContent": {
"_uniqueProp": "033_PS3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "033",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178237",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178237",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--M"
},
{
"entContent": {
"_uniqueProp": "033_PM3_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "033",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178228",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178228",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--L"
},
{
"entContent": {
"_uniqueProp": "033_PS2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in _SLC9A6_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "033",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178226",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178226",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--I"
},
{
"entContent": {
"_uniqueProp": "033_PS4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases. However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "033",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178225",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178225",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--J"
},
{
"entContent": {
"_uniqueProp": "033_PP2_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "033",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178223",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178223",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--F"
},
{
"entContent": {
"_uniqueProp": "033_PM1_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "033",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178222",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178222",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--E"
},
{
"entContent": {
"_uniqueProp": "033_PP4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "033",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178218",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178218",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--H"
},
{
"entContent": {
"_uniqueProp": "033_BP6_nuclear_SLC9A6",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "033",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178242",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178242",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--Q"
},
{
"entContent": {
"_uniqueProp": "033_BP2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _SLC9A6_ results in disease but viable phenotype.[4](#pmid_21964919)",
"label": "BP2",
"ns": "033",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for SLC9A6 for _in trans_ state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178235",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178235",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--K"
},
{
"entContent": {
"_uniqueProp": "033_PM6_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in _SLC9A6_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "033",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178233",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178233",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--I"
},
{
"entContent": {
"_uniqueProp": "033_BA1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "033",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178227",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178227",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--K"
},
{
"entContent": {
"_uniqueProp": "033_PP3_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "033",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178224",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178224",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpC--G"
},
{
"entContent": {
"_uniqueProp": "033_BS2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "033",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) hemizygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) hemizygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178219",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178219",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--C"
},
{
"entContent": {
"_uniqueProp": "033_PVS1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "For intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.",
"label": "PVS1",
"ns": "033",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single exon in-frame deletion predicted to preserve the reading frame (exon 10), and multiple in-frame exon deletions that include exon 10.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).[2](#PMID_27256868),[3](#PMID_19377476),[1](#PMID_18342287)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _SLC9A6_",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178240",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178240",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--O"
},
{
"entContent": {
"_uniqueProp": "033_BP4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "033",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178238",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178238",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpC--I"
},
{
"entContent": {
"_uniqueProp": "033_BP3_nuclear_SLC9A6",
"additionalComments": "Not applicable for SLC9A6.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "033",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178236",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178236",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--L"
},
{
"entContent": {
"_uniqueProp": "033_PS1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "033",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178234",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178234",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--J"
},
{
"entContent": {
"_uniqueProp": "033_BS1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles \\[assumes 50/50 male/female ratio\\]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "033",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178229",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178229",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--J"
},
{
"entContent": {
"_uniqueProp": "033_PM2_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "033",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178217",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178217",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpO--G"
},
{
"entContent": {
"_uniqueProp": "033_BP7_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "033",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178244",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178244",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxpS---"
},
{
"entContent": {
"_uniqueProp": "033_PP5_nuclear_SLC9A6",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "033",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178243",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178243",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--K"
},
{
"entContent": {
"_uniqueProp": "033_PP1_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "033",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178239",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178239",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxoy--N"
},
{
"entContent": {
"_uniqueProp": "033_PM4_nuclear_SLC9A6",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SLC9A6"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "033",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572178230",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572178230",
"modified": "2023-05-09T17:23:42.609Z",
"modifier": "arossel",
"rev": "_h6SHxo6--G"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010278",
"lbl": "Christianson syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010278"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/christianson_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/intellectual_developmental_disorder_x_linked_syndromic_christianson_type"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015159"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0016612"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10572/christianson-syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/394455"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C567484"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/702354007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2678194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060825"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_85278"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/300243"
}
],
"definition": {
"val": "A very rare form of syndromic intellectual deficit characterized by microcephaly, severe developmental delay or regression, hypotonia, abnormal movements, and early-onset seizures.",
"xrefs": [
"Orphanet:85278"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Christianson syndrome",
"xrefs": [
"DOID:0060825",
"Orphanet:85278"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MRXSCH",
"xrefs": [
"DOID:0060825",
"MONDO:Lexical",
"OMIM:300243"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked Angelman-like syndrome",
"xrefs": [
"DOID:0060825",
"Orphanet:85278"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked intellectual disability, South African type",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"val": "X-linked intellectual disability-craniofacial dysmorphism-epilepsy-ophthalmoplegia-cerebellar atrophy syndrome",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"val": "intellectual developmental disorder, X-linked syndromic, Christianson type"
},
{
"pred": "hasExactSynonym",
"val": "intellectual disability, X-linked syndromic, Christianson type"
},
{
"pred": "hasExactSynonym",
"val": "intellectual disability, microcephaly, epilepsy, and ataxia syndrome"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked syndromic, Christianson type",
"xrefs": [
"DOID:0060825"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, microcephaly, epilepsy, and ataxia syndrome",
"xrefs": [
"DOID:0060825",
"OMIM:300243"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman-like syndrome X-linked",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman-like syndrome, X-linked"
},
{
"pred": "hasRelatedSynonym",
"val": "MRXS Christianson",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "X-linked intellectual disability - craniofacial dysmorphism - epilepsy - ophthalmoplegia - cerebellar atrophy",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability X-linked syndromic Christianson type",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability microcephaly epilepsy and ataxia syndrome",
"xrefs": [
"GARD:0010572"
]
},
{
"pred": "hasRelatedSynonym",
"val": "intellectual disability, X-linked, syndromic, Christianson type",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "mental retardation, X-linked, syndromic, Christianson type",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0060825"
},
{
"val": "GARD:10572"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:394455"
},
{
"val": "MESH:C567484"
},
{
"val": "OMIM:300243"
},
{
"val": "Orphanet:85278"
},
{
"val": "SCTID:702354007"
},
{
"val": "UMLS:C2678194"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010278",
"name": "Christianson syndrome",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0010278",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010278",
"entType": "Disease",
"ldhId": "135642212",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642212",
"modified": "2025-10-07T15:44:09.019Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WHly---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963049980000,
"agr": "HGNC:11079",
"alias_symbol": [
"NHE6",
"KIAA0267"
],
"bioparadigms_slc": "SLC9A6",
"ccds_id": [
"CCDS55504",
"CCDS44003",
"CCDS83492",
"CCDS14654"
],
"date_approved_reserved": "1999-07-30",
"date_modified": "2020-04-02",
"date_name_changed": "2016-02-25",
"ena": [
"AF030409"
],
"ensembl_gene_id": "ENSG00000198689",
"entrez_id": "10479",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:11079",
"iuphar": "objectId:953",
"location": "Xq26.3",
"location_sortable": "Xq26.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SLC9A6"
],
"mane_select": [
"ENST00000630721.3",
"NM_001379110.1"
],
"mgd_id": [
"MGI:2443511"
],
"name": "solute carrier family 9 member A6",
"omim_id": [
"300231"
],
"orphanet": 158415,
"prev_name": [
"solute carrier family 9 (sodium/hydrogen exchanger), isoform 6",
"solute carrier family 9 (sodium/hydrogen exchanger), member 6",
"solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6"
],
"pubmed_id": [
9507001
],
"refseq_accession": [
"NM_006359"
],
"rgd_id": [
"RGD:1563582"
],
"status": "Approved",
"symbol": "SLC9A6",
"ucsc_id": "uc004ezk.4",
"uniprot_ids": [
"Q92581"
],
"uuid": "b6c70e29-8831-4056-bece-f6ea1bebac3c",
"vega_id": "OTTHUMG00000022498"
},
"NCBI": {
"id": "10479"
}
},
"entId": "SLC9A6",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11079",
"entType": "Gene",
"ldhId": "135641940",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641940",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "033_nuclear_SLC9A6",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0010278",
"preferredTitle": "Christianson syndrome"
}
],
"gene": "SLC9A6",
"preferredTranscript": "NM_006359.2"
}
],
"ns": "033",
"references": [
{
"auths": [
"Gilfillan GD",
"Selmer KK",
"et al."
],
"doiStr": "10.1016/j.ajhg.2008.01.013",
"id": "18342287",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. 1003-10.",
"source": "Am J Hum Genet",
"title": "SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.",
"vol": "82",
"year": "2008"
},
{
"auths": [
"Masurel-Paulet A",
"Piton A",
"et al."
],
"doiStr": "10.1002/ajmg.a.37765",
"id": "27256868",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 2103-10.",
"source": "Am J Med Genet A",
"title": "A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.",
"vol": "170",
"year": "2016"
},
{
"auths": [
"Tarpey PS",
"Smith R",
"et al."
],
"doiStr": "10.1038/ng.367",
"id": "19377476",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 535-43.",
"source": "Nat Genet",
"title": "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.",
"vol": "41",
"year": "2009"
},
{
"auths": [
"Strømme P",
"Dobrenis K",
"et al."
],
"doiStr": "10.1093/brain/awr250",
"id": "21964919",
"iss": "(Pt 11)",
"namespace": "pmid",
"pages": "p. 3369-83.",
"source": "Brain",
"title": "X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction.",
"vol": "134",
"year": "2011"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule13, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243110",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243110",
"modified": "2023-05-09T17:23:42.532Z",
"modifier": "arossel",
"rev": "_h6SHyTW--u"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
}
]
},
"ldhId": "643243103",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243103",
"modified": "2023-09-29T15:16:49.367Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---E"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:20.029Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN034",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:25.125Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:29:08.581Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:29.320Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:50:54.202Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:20.029Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-08-09T16:35:12.943Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"034"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN034",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "034_PS4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "034",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179047",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179047",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxoy--U"
},
{
"entContent": {
"_uniqueProp": "034_PM5_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "034",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* Applicable to all genes as written.\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179043",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179043",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxo6--L"
},
{
"entContent": {
"_uniqueProp": "034_BP6_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "034",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179064",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179064",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--E"
},
{
"entContent": {
"_uniqueProp": "034_BP4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "034",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179060",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179060",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpW--L"
},
{
"entContent": {
"_uniqueProp": "034_BP2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _CDKL5_ results in disease but viable phenotype.[5](#PMID_23236174)",
"label": "BP2",
"ns": "034",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for _in trans_ state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179057",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179057",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--C"
},
{
"entContent": {
"_uniqueProp": "034_BS3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "034",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179042",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179042",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--_"
},
{
"entContent": {
"_uniqueProp": "034_PM2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM2",
"ns": "034",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179039",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179039",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxoy--R"
},
{
"entContent": {
"_uniqueProp": "034_PVS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* Do not use PVS1 for truncating variants in _CDKL5_ C-terminus (exons 19-21, or after p.P904) **when using the historically used transcript (NM\\_003159.2).**\n* _CDKL5_ (exon 1) is non-coding exons. There is evidence that loss of just non-coding _CDKL5_ exon 1 is pathogenic given previous de novo finding in patients affected with CDKL5-disease (GeneDx internal data), therefore, for losses involving just _CDKL5_ exon 1, PVS1 can be applied.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1\n* Given the extensive data available for _CDKL5_, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Exceptions are _CDKL5_ exon 17 (as described above) due to a limited number of pathogenic variants reported to date.",
"label": "PVS1",
"ns": "034",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.R948 **when using the major brain isoform which has an alternative C-terminus (NM\\_001323289.2)**, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.R948.(**when using the major brain isoform, NM\\_001323289.2**) and for canonical splice site variants that flank exon 17 (in-frame exon).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _CDKL5._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179062",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179062",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxoy--V"
},
{
"entContent": {
"_uniqueProp": "034_PS3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "034",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179059",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179059",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpC--L"
},
{
"entContent": {
"_uniqueProp": "034_PM6_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in _CDKL5_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "034",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179055",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179055",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpW--J"
},
{
"entContent": {
"_uniqueProp": "034_BP1_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "034",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179053",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179053",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpC--K"
},
{
"entContent": {
"_uniqueProp": "034_PM4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "034",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) (when using the NM\\_003159.2 transcript).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179052",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179052",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxp----"
},
{
"entContent": {
"_uniqueProp": "034_BS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles \\[assumes 50/50 male/female ratio\\]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "034",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency greater than expected for disease (0.025%).\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179051",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179051",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxo6--R"
},
{
"entContent": {
"_uniqueProp": "034_PS2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). Because of the very high de novo rate of pathogenic variants in _CDKL5_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "034",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\\\\\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179048",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179048",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxo6--O"
},
{
"entContent": {
"_uniqueProp": "034_BP7_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "034",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179066",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179066",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxp---A"
},
{
"entContent": {
"_uniqueProp": "034_PP5_nuclear_CDKL5",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "034",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179065",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179065",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpG---"
},
{
"entContent": {
"_uniqueProp": "034_BP5_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _CKDL5_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "034",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179063",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179063",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpC--M"
},
{
"entContent": {
"_uniqueProp": "034_PS1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "034",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179056",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179056",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpW--K"
},
{
"entContent": {
"_uniqueProp": "034_BS4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "034",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179054",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179054",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--B"
},
{
"entContent": {
"_uniqueProp": "034_BA1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "034",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency above 0.05%.\n* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179049",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179049",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpW--I"
},
{
"entContent": {
"_uniqueProp": "034_PP2_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "034",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179045",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179045",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpC--J"
},
{
"entContent": {
"_uniqueProp": "034_PP1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "034",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179061",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179061",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxp---_"
},
{
"entContent": {
"_uniqueProp": "034_BP3_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "034",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179058",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179058",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--D"
},
{
"entContent": {
"_uniqueProp": "034_PM3_nuclear_CDKL5",
"additionalComments": "Not applicable for CDKL5.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "034",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179050",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179050",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxo6--P"
},
{
"entContent": {
"_uniqueProp": "034_PP3_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "034",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179046",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179046",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxoy--T"
},
{
"entContent": {
"_uniqueProp": "034_PM1_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "034",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171[1](#PMID_28544139),[4](#PMID_17993579),[2](#PMID_23064044),[3](#PMID_29264392)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179044",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179044",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpS--A"
},
{
"entContent": {
"_uniqueProp": "034_BS2_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "034",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes or hemizygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote or hemizygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179041",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179041",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxpW--H"
},
{
"entContent": {
"_uniqueProp": "034_PP4_nuclear_CDKL5",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"CDKL5"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "034",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179040",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179040",
"modified": "2023-05-09T17:24:20.629Z",
"modifier": "arossel",
"rev": "_h6SHxoy--S"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100039",
"lbl": "CDKL5 disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/202"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100039"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000594"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0017656"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:32:48Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
}
],
"comments": [
"Subtypes of the heterogeneous, eponymously named Early Infantile Epileptic Encephalopathy, Atypical Rett Syndrome, West Syndrome are caused by mutations in the gene CDKL5. The common and most penetrant phenotype shared among these disease entities is early onset epilepsy, progressive microcephaly, dysmorphic facial features, and intellectual disability, with stereotypic hand movements, respiratory impairment with breath holding and hyperventilation having variable phenotypic expressivity. (https://orcid.org/0000-0002-6733-369X)"
],
"definition": {
"val": "A monogenic disease that has material basis in mutation in the CDKL5 gene.",
"xrefs": [
"PMID:21154482",
"PMID:22872100",
"PMID:27080038",
"PMID:27528505"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "CDKL5 Deficiency Disorder",
"xrefs": [
"NORD:904"
]
},
{
"pred": "hasExactSynonym",
"val": "CDKL5 disorder"
},
{
"pred": "hasExactSynonym",
"val": "CDKL5 inherited genetic disease",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "inherited genetic disease caused by mutation in CDKL5",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CDKL5",
"xrefs": [
"GARD:0012173"
]
},
{
"pred": "hasRelatedSynonym",
"val": "CDKL5-related disorder",
"xrefs": [
"GARD:0012173"
]
}
],
"xrefs": [
{
"val": "NORD:904"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100039",
"name": "CDKL5 disorder",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0100039",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100039",
"entType": "Disease",
"ldhId": "135642215",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642215",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjS---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056944354918400,
"agr": "HGNC:11411",
"alias_symbol": [
"EIEE2",
"CFAP247"
],
"ccds_id": [
"CCDS14186",
"CCDS83458"
],
"date_approved_reserved": "1997-10-27",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-07",
"date_symbol_changed": "2002-11-29",
"ena": [
"Y15057"
],
"ensembl_gene_id": "ENSG00000008086",
"entrez_id": "6792",
"gene_group": [
"Cyclin dependent kinases",
"Cilia and flagella associated"
],
"gene_group_id": [
496,
1491
],
"hgnc_id": "HGNC:11411",
"iuphar": "objectId:1986",
"location": "Xp22.13",
"location_sortable": "Xp22.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/CDKL5"
],
"mane_select": [
"ENST00000623535.2",
"NM_001323289.2"
],
"mgd_id": [
"MGI:1278336"
],
"name": "cyclin dependent kinase like 5",
"omim_id": [
"300203"
],
"orphanet": 119297,
"prev_name": [
"serine/threonine kinase 9",
"cyclin-dependent kinase-like 5"
],
"prev_symbol": [
"STK9"
],
"pubmed_id": [
9721213,
16935860
],
"refseq_accession": [
"NM_003159"
],
"rgd_id": [
"RGD:2324133"
],
"status": "Approved",
"symbol": "CDKL5",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004cyn.4",
"uniprot_ids": [
"O76039"
],
"uuid": "e2ddada8-4549-4565-aacb-21ae135a19ab",
"vega_id": "OTTHUMG00000021214"
},
"NCBI": {
"id": "6792"
}
},
"entId": "CDKL5",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11411",
"entType": "Gene",
"ldhId": "135641943",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641943",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB----"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "034_nuclear_CDKL5",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100039",
"preferredTitle": "CDKL5 disorder"
}
],
"gene": "CDKL5",
"preferredTranscript": "NM_001323289.2"
}
],
"ns": "034",
"references": [
{
"auths": [
"Krishnaraj R",
"Ho G",
"et al."
],
"doiStr": "10.1002/humu.23263",
"id": "28544139",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 922-931.",
"source": "Hum Mutat",
"title": "RettBASE: Rett syndrome database update.",
"vol": "38",
"year": "2017"
},
{
"auths": [
"Raymond L",
"Diebold B",
"et al."
],
"doiStr": "10.1016/j.gene.2012.09.056",
"id": "23064044",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 70-5.",
"source": "Gene",
"title": "Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene: identification of novel mutations.",
"vol": "512",
"year": "2013"
},
{
"auths": [
"Hector RD",
"Kalscheuer VM",
"et al."
],
"doiStr": "10.1212/NXG.0000000000000200",
"id": "29264392",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. e200.",
"source": "Neurol Genet",
"title": "CDKL5 variants: Improving our understanding of a rare neurologic disorder.",
"vol": "3",
"year": "2017"
},
{
"auths": [
"Rosas-Vargas H",
"Bahi-Buisson N",
"et al."
],
"doiStr": "10.1136/jmg.2007.053504",
"id": "17993579",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 172-8.",
"source": "J Med Genet",
"title": "Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy.",
"vol": "45",
"year": "2008"
},
{
"auths": [
"Wang IT",
"Allen M",
"et al."
],
"doiStr": "10.1073/pnas.1216988110",
"id": "23236174",
"iss": "(52)",
"namespace": "pmid",
"pages": "p. 21516-21.",
"source": "Proc Natl Acad Sci U S A",
"title": "Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.",
"vol": "109",
"year": "2012"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule13, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243111",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243111",
"modified": "2023-05-09T17:24:20.544Z",
"modifier": "arossel",
"rev": "_h6SHyTS--T"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
}
]
},
"ldhId": "643243104",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243104",
"modified": "2024-08-09T16:35:13.387Z",
"modifier": "cspecVcepCoordinatorTest",
"rev": "_iRd8f2K---"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:24:47.151Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN035",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:29.035Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:49.658Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-08T20:17:49.295Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:06.342Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:24:47.151Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"035"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN035",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "035_BP6_nuclear_FOXG1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "035",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179858",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179858",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxo2--C"
},
{
"entContent": {
"_uniqueProp": "035_PM4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "035",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179846",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179846",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--C"
},
{
"entContent": {
"_uniqueProp": "035_PM3_nuclear_FOXG1",
"additionalComments": "Not applicable for FOXG1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "035",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179844",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179844",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--A"
},
{
"entContent": {
"_uniqueProp": "035_BA1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "035",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179843",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179843",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxo2---"
},
{
"entContent": {
"_uniqueProp": "035_PP2_nuclear_FOXG1",
"additionalComments": "Not applicable for FOXG1.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "035",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179839",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179839",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxp---C"
},
{
"entContent": {
"_uniqueProp": "035_PM1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM1",
"ns": "035",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Forkhead: aa 181-275[7](#PMID_18571142),[8](#PMID_28661489)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179838",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179838",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--A"
},
{
"entContent": {
"_uniqueProp": "035_BS3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "035",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179836",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179836",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxp---B"
},
{
"entContent": {
"_uniqueProp": "035_PM2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "If PVS1 is also applicable, variant can be classified as likely pathogenic",
"label": "PM2",
"ns": "035",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179833",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179833",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxoy--W"
},
{
"entContent": {
"_uniqueProp": "035_BP5_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _FOXG1_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "035",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179857",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179857",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--D"
},
{
"entContent": {
"_uniqueProp": "035_BP3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "035",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In-frame deletions/insertions in a repetitive region without a known function\n\n* Inframe expansions or deletions in _FOXG1_ repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179852",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179852",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpS--F"
},
{
"entContent": {
"_uniqueProp": "035_PS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "035",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179850",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179850",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxo2--_"
},
{
"entContent": {
"_uniqueProp": "035_PM6_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM6",
"ns": "035",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179849",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179849",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--E"
},
{
"entContent": {
"_uniqueProp": "035_PS2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in FOXG1, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "035",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179842",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179842",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--B"
},
{
"entContent": {
"_uniqueProp": "035_PS4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "035",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179841",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179841",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxoy--Y"
},
{
"entContent": {
"_uniqueProp": "035_PP3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "035",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179840",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179840",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxoy--X"
},
{
"entContent": {
"_uniqueProp": "035_BP7_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "035",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179860",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179860",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--E"
},
{
"entContent": {
"_uniqueProp": "035_PP5_nuclear_FOXG1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "035",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179859",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179859",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--G"
},
{
"entContent": {
"_uniqueProp": "035_PP1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "035",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179855",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179855",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxp---E"
},
{
"entContent": {
"_uniqueProp": "035_BS2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "035",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179835",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179835",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa---"
},
{
"entContent": {
"_uniqueProp": "035_BP4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "035",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179854",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179854",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxo2--B"
},
{
"entContent": {
"_uniqueProp": "035_BS4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "035",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179848",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179848",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--D"
},
{
"entContent": {
"_uniqueProp": "035_BS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles \\[assumes 50/50 male/female ratio\\]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "035",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179845",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179845",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--B"
},
{
"entContent": {
"_uniqueProp": "035_PVS1_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "035",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.S468[1](#PMID_30525188)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Strong is applicable for any truncating variant from p.G469 to p.Q480[6](#PMID_29655203).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.Q480.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Supporting is applicable for initiation codon variants in _FOXG1._",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179856",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179856",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--F"
},
{
"entContent": {
"_uniqueProp": "035_PS3_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "035",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179853",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179853",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--C"
},
{
"entContent": {
"_uniqueProp": "035_BP2_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"instructionsToUse": "Knock-out results in embryonic lethality/drastic phenotype[9](#PMID_14704420)",
"label": "BP2",
"ns": "035",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* Applicable for _in trans_ state",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179851",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179851",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxo2--A"
},
{
"entContent": {
"_uniqueProp": "035_BP1_nuclear_FOXG1",
"additionalComments": "Not applicable for FOXG1.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "035",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179847",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179847",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxp---D"
},
{
"entContent": {
"_uniqueProp": "035_PM5_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "035",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179837",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179837",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpa--_"
},
{
"entContent": {
"_uniqueProp": "035_PP4_nuclear_FOXG1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"FOXG1"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "035",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572179834",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572179834",
"modified": "2023-05-09T17:24:47.776Z",
"modifier": "arossel",
"rev": "_h6SHxpG--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100040",
"lbl": "FOXG1 disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4069"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7850"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100040"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/foxg1_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/foxg1_syndrome_due_to_intragenic_alteration"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rett_syndrome_congenital_variant"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T19:29:48Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#broadMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/F84.8"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1842594"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5681589"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C176903"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_561854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_598164"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/613454"
}
],
"comments": [
"Subtypes of the heterogeneous, eponymously named Congenital variant of Rett Syndrome, and Atypical Rett Syndrome are caused by mutations in the gene FOXG1. The common and most penetrant phenotype shared among these disease entities is neurodevelopmental impairment present in early infancy, progressive microcephaly, and MRI of the brain showing reduced myelinization and/or abnormal corpus callosum. Stereotypic hand movements, epilepsy, and abnormal breathing can have variable phenotypic expressivity. (https://orcid.org/0000-0002-6733-369X)"
],
"definition": {
"val": "A monogenic disease that has material basis in mutation in the FOXG1 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "FOXG1 disorder"
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 inherited genetic disease",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 syndrome",
"xrefs": [
"MONDO:0035383"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1 syndrome due to intragenic alteration",
"xrefs": [
"MONDO:0035713"
]
},
{
"pred": "hasExactSynonym",
"val": "FOXG1-related epileptic-dyskinetic encephalopathy",
"xrefs": [
"Orphanet:561854"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, congenital variant",
"xrefs": [
"MONDO:0013270",
"NCIT:C176903",
"OMIM:613454"
]
},
{
"pred": "hasExactSynonym",
"val": "inherited genetic disease caused by mutation in FOXG1"
}
],
"xrefs": [
{
"val": "ICD10CM:F84.8"
},
{
"val": "MEDGEN:1842594"
},
{
"val": "NCIT:C176903"
},
{
"val": "OMIM:613454"
},
{
"val": "Orphanet:561854"
},
{
"val": "Orphanet:598164"
},
{
"val": "UMLS:C5681589"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100040",
"name": "FOXG1 disorder",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0100040",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100040",
"entType": "Disease",
"ldhId": "135642211",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642211",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFji---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056947891765200,
"agr": "HGNC:3811",
"alias_name": [
"brain factor 1"
],
"alias_symbol": [
"HFK2",
"QIN",
"BF1",
"HFK1",
"HFK3",
"HBF-3"
],
"ccds_id": [
"CCDS9636"
],
"date_approved_reserved": "1994-12-07",
"date_modified": "2021-05-26",
"date_name_changed": "2007-05-16",
"date_symbol_changed": "2007-05-16",
"ensembl_gene_id": "ENSG00000176165",
"entrez_id": "2290",
"gene_group": [
"Forkhead boxes"
],
"gene_group_id": [
508
],
"hgnc_id": "HGNC:3811",
"location": "14q12",
"location_sortable": "14q12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000313071.7",
"NM_005249.5"
],
"mgd_id": [
"MGI:1347464"
],
"name": "forkhead box G1",
"omim_id": [
"164874"
],
"orphanet": 167854,
"prev_name": [
"forkhead box G1B",
"forkhead box G1C",
"forkhead box G1A"
],
"prev_symbol": [
"FKHL2",
"FOXG1B",
"FKHL4",
"FKH2",
"FKHL1",
"FOXG1C",
"FKHL3",
"FOXG1A"
],
"pubmed_id": [
7959731,
17260156
],
"refseq_accession": [
"NM_005249"
],
"rgd_id": [
"RGD:2619"
],
"status": "Approved",
"symbol": "FOXG1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wqe.5",
"uniprot_ids": [
"P55316"
],
"uuid": "14559109-ad8e-40f8-bf17-ebb1f1e0bd99",
"vega_id": "OTTHUMG00000140187"
},
"NCBI": {
"id": "2290"
}
},
"entId": "FOXG1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3811",
"entType": "Gene",
"ldhId": "135641939",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641939",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "035_nuclear_FOXG1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100040",
"preferredTitle": "FOXG1 disorder"
}
],
"gene": "FOXG1",
"preferredTranscript": "NM_005249.4"
}
],
"ns": "035",
"references": [
{
"auths": [
"Snoeijen-Schouwenaars FM",
"van Ool JS",
"et al."
],
"doiStr": "10.1111/epi.14618",
"id": "30525188",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 155-164.",
"source": "Epilepsia",
"title": "Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.",
"vol": "60",
"year": "2019"
},
{
"auths": [
"Lindy AS",
"Stosser MB",
"et al."
],
"doiStr": "10.1111/epi.14074",
"id": "29655203",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 1062-1071.",
"source": "Epilepsia",
"title": "Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.",
"vol": "59",
"year": "2018"
},
{
"auths": [
"Mitter D",
"Pringsheim M",
"et al."
],
"doiStr": "10.1038/gim.2017.75",
"id": "28661489",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 98-108.",
"source": "Genet Med",
"title": "FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.",
"vol": "20",
"year": "2018"
},
{
"auths": [
"Ariani F",
"Hayek G",
"et al."
],
"doiStr": "10.1016/j.ajhg.2008.05.015",
"id": "18571142",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 89-93.",
"source": "Am J Hum Genet",
"title": "FOXG1 is responsible for the congenital variant of Rett syndrome.",
"vol": "83",
"year": "2008"
},
{
"auths": [
"Hanashima C",
"Li SC",
"et al."
],
"doiStr": "10.1126/science.1090674",
"id": "14704420",
"iss": "(5654)",
"namespace": "pmid",
"pages": "p. 56-9.",
"source": "Science",
"title": "Foxg1 suppresses early cortical cell fate.",
"vol": "303",
"year": "2004"
},
{
"auths": [
"Lindy AS",
"Stosser MB",
"et al."
],
"doiStr": "10.1111/epi.14074",
"id": "29655203",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 1062-1071.",
"source": "Epilepsia",
"title": "Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.",
"vol": "59",
"year": "2018"
},
{
"auths": [
"Ariani F",
"Hayek G",
"et al."
],
"doiStr": "10.1016/j.ajhg.2008.05.015",
"id": "18571142",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 89-93.",
"source": "Am J Hum Genet",
"title": "FOXG1 is responsible for the congenital variant of Rett syndrome.",
"vol": "83",
"year": "2008"
},
{
"auths": [
"Mitter D",
"Pringsheim M",
"et al."
],
"doiStr": "10.1038/gim.2017.75",
"id": "28661489",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 98-108.",
"source": "Genet Med",
"title": "FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.",
"vol": "20",
"year": "2018"
},
{
"auths": [
"Hanashima C",
"Li SC",
"et al."
],
"doiStr": "10.1126/science.1090674",
"id": "14704420",
"iss": "(5654)",
"namespace": "pmid",
"pages": "p. 56-9.",
"source": "Science",
"title": "Foxg1 suppresses early cortical cell fate.",
"vol": "303",
"year": "2004"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP3",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243112",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243112",
"modified": "2023-05-09T17:24:47.691Z",
"modifier": "arossel",
"rev": "_h6SHyTS--Z"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
}
]
},
"ldhId": "643243105",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243105",
"modified": "2023-09-29T15:16:49.547Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--K"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:03.587Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN036",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"releasedUnderRevision": true,
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:33.027Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:28:31.618Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:18.754Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:03.587Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-03-05T20:41:20.182Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"036"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0",
"version": "3.0.0",
"versioned": true
},
"entId": "GN036",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "036_PVS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Initiation codon variants are not applicable due to the MECP2E1 alternative isoform that excludes exon 1 with an alterante start codon.\n\nFor intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions, assign the same strength (PVS1 or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions, PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for MECP2, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "036",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* PVS1\\_Moderate is applicable for any truncating variant distal of p.E472.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180613",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180613",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--I"
},
{
"entContent": {
"_uniqueProp": "036_BP4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "036",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180611",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180611",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpW--_"
},
{
"entContent": {
"_uniqueProp": "036_BP2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of MECP2 results in embryonic lethality/drastic phenotype.[1](#PMID_11242117)",
"label": "BP2",
"ns": "036",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180608",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180608",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--K"
},
{
"entContent": {
"_uniqueProp": "036_BS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles \\[assumes 50/50 male/female ratio\\]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "036",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180602",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180602",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpS--G"
},
{
"entContent": {
"_uniqueProp": "036_PM3_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "036",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180601",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180601",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--I"
},
{
"entContent": {
"_uniqueProp": "036_PS4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (RettBASE). However, independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "036",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180598",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180598",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--H"
},
{
"entContent": {
"_uniqueProp": "036_PS1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "036",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180607",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180607",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---L"
},
{
"entContent": {
"_uniqueProp": "036_PM4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "036",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in _MECP2_, as several stop loss variants in this gene has been described in affected individuals.[2](#PMID_11469283)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene (p.381-p.405)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n* Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180603",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180603",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--F"
},
{
"entContent": {
"_uniqueProp": "036_BP7_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "036",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180617",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180617",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--K"
},
{
"entContent": {
"_uniqueProp": "036_BP5_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "* For example, if a variant in MECP2 is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the PAFAH1B1 gene.\n* Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply for any gene if variant is de novo.",
"label": "BP5",
"ns": "036",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180614",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180614",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--L"
},
{
"entContent": {
"_uniqueProp": "036_PP1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Note: Individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "036",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180612",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180612",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpG--I"
},
{
"entContent": {
"_uniqueProp": "036_BP1_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "036",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180604",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180604",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--J"
},
{
"entContent": {
"_uniqueProp": "036_BA1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "036",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180600",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180600",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---J"
},
{
"entContent": {
"_uniqueProp": "036_PS2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "036",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180599",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180599",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---I"
},
{
"entContent": {
"_uniqueProp": "036_PP3_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "036",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180597",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180597",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--E"
},
{
"entContent": {
"_uniqueProp": "036_BS3_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "036",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180593",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180593",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---G"
},
{
"entContent": {
"_uniqueProp": "036_PM2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "036",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180590",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180590",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---F"
},
{
"entContent": {
"_uniqueProp": "036_PP5_nuclear_MECP2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "036",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180616",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180616",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpW--B"
},
{
"entContent": {
"_uniqueProp": "036_BP3_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "036",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180609",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180609",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpW---"
},
{
"entContent": {
"_uniqueProp": "036_PM6_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in MECP2, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "036",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. \n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Confirmed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180606",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180606",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--G"
},
{
"entContent": {
"_uniqueProp": "036_BS4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "036",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180605",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180605",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---K"
},
{
"entContent": {
"_uniqueProp": "036_PP2_nuclear_MECP2",
"additionalComments": "Not applicable for MECP2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "036",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180596",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180596",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpG--H"
},
{
"entContent": {
"_uniqueProp": "036_PM1_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "036",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* Methyl-DNA binding (MBD): aa 90-162\n* Transcirptional repression domain (TRD): aa 302-306",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180595",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180595",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxp---H"
},
{
"entContent": {
"_uniqueProp": "036_PM5_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "036",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180594",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180594",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--G"
},
{
"entContent": {
"_uniqueProp": "036_BS2_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "* Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes.\n* Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "036",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related or unrelated) heterozygotes or hemizygotes.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 1 unaffected (related or unrelated) heterozygote or hemizygote",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180592",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180592",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxpa--F"
},
{
"entContent": {
"_uniqueProp": "036_PP4_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "036",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180591",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180591",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--D"
},
{
"entContent": {
"_uniqueProp": "036_BP6_nuclear_MECP2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "036",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180615",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180615",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--J"
},
{
"entContent": {
"_uniqueProp": "036_PS3_nuclear_MECP2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"MECP2"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "036",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n* RNA studies that demonstrate abnormal splicing and an out-offrame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for approved functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1572180610",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1572180610",
"modified": "2023-05-09T17:25:04.245Z",
"modifier": "arossel",
"rev": "_h6SHxo2--H"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010726",
"lbl": "Rett syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010726"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rett_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015653"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0017656"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020119"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10039000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/201200685"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/48441"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D015518"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/68618008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0035372"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1206"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C75488"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_778"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/312750"
}
],
"definition": {
"val": "A severe neurodevelopmental disorder affecting the central nervous system.",
"xrefs": [
"Orphanet:778"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "RTS",
"xrefs": [
"OMIM:312750"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "RTT",
"xrefs": [
"MONDO:Lexical",
"OMIM:312750"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome",
"xrefs": [
"DOID:1206",
"MONDO:Lexical",
"NCIT:C75488",
"OMIM:312750",
"Orphanet:778"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, atypical, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett syndrome, preserved speech variant, X-linked dominant"
},
{
"pred": "hasExactSynonym",
"val": "Rett's disorder",
"xrefs": [
"DOID:1206"
]
},
{
"pred": "hasExactSynonym",
"val": "Rett’s disease",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"val": "cerebroatrophic hyperammonemia",
"xrefs": [
"DOID:1206"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, Zappella variant"
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, atypical"
},
{
"pred": "hasRelatedSynonym",
"val": "Rett syndrome, preserved speech variant"
},
{
"pred": "hasRelatedSynonym",
"val": "autism, dementia, ataxia, and loss of purposeful hand use"
}
],
"xrefs": [
{
"val": "DOID:1206"
},
{
"val": "GARD:5696"
},
{
"val": "ICD9:330.8"
},
{
"val": "MEDGEN:48441"
},
{
"val": "MESH:D015518"
},
{
"val": "MedDRA:10039000"
},
{
"val": "NANDO:1200603"
},
{
"val": "NANDO:1200604"
},
{
"val": "NANDO:2100219"
},
{
"val": "NANDO:2200825"
},
{
"val": "NCIT:C75488"
},
{
"val": "NORD:1666"
},
{
"val": "OMIM:312750"
},
{
"val": "Orphanet:778"
},
{
"val": "SCTID:68618008"
},
{
"val": "UMLS:C0035372"
},
{
"val": "icd11.foundation:201200685"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010726",
"name": "Rett syndrome",
"preferredModeOfInheritance": {
"inheritance": "X-linked inheritance",
"sepioID": "HP:0001417"
}
},
"entId": "MONDO:0010726",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010726",
"entType": "Disease",
"ldhId": "135642210",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642210",
"modified": "2025-10-07T15:44:17.321Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WPjK---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056953001476000,
"agr": "HGNC:6990",
"ccds_id": [
"CCDS14741",
"CCDS48193"
],
"date_approved_reserved": "1996-09-03",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-13",
"ena": [
"AF158180"
],
"ensembl_gene_id": "ENSG00000169057",
"entrez_id": "4204",
"gene_group": [
"Methyl-CpG binding domain containing"
],
"gene_group_id": [
1025
],
"hgnc_id": "HGNC:6990",
"location": "Xq28",
"location_sortable": "Xq28",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"RettBASE|http://mecp2.chw.edu.au/",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/MECP2",
"LRG_764|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_764.xml"
],
"mane_select": [
"ENST00000453960.7",
"NM_001110792.2"
],
"mgd_id": [
"MGI:99918"
],
"name": "methyl-CpG binding protein 2",
"omim_id": [
"300005"
],
"orphanet": 123186,
"prev_name": [
"mental retardation, X-linked 16",
"mental retardation, X-linked 79",
"Rett syndrome",
"methyl CpG binding protein 2 (Rett syndrome)",
"methyl CpG binding protein 2"
],
"prev_symbol": [
"RTT",
"MRX16",
"MRX79"
],
"pubmed_id": [
1606614,
10508514
],
"refseq_accession": [
"NM_004992"
],
"rgd_id": [
"RGD:3075"
],
"status": "Approved",
"symbol": "MECP2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004fjv.3",
"uniprot_ids": [
"P51608"
],
"uuid": "c911c5cc-315e-4631-bcdd-8627c7cc337c",
"vega_id": "OTTHUMG00000024229"
},
"NCBI": {
"id": "4202"
}
},
"entId": "MECP2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6990",
"entType": "Gene",
"ldhId": "135641938",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641938",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "036_nuclear_MECP2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0010726",
"preferredTitle": "Rett syndrome"
}
],
"gene": "MECP2",
"preferredTranscript": "NM_004992.3"
}
],
"ns": "036",
"references": [
{
"auths": [
"Guy J",
"Hendrich B",
"et al."
],
"doiStr": "10.1038/85899",
"id": "11242117",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 322-6.",
"source": "Nat Genet",
"title": "A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.",
"vol": "27",
"year": "2001"
},
{
"auths": [
"Erlandson A",
"Hallberg B",
"et al."
],
"doiStr": "10.1007/s007870170034",
"id": "11469283",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 117-21.",
"source": "Eur Child Adolesc Psychiatry",
"title": "MECP2 mutation screening in Swedish classical Rett syndrome females.",
"vol": "10",
"year": "2001"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243113",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243113",
"modified": "2023-05-09T17:25:04.170Z",
"modifier": "arossel",
"rev": "_h6SHyTS--b"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243106",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243106",
"modified": "2024-03-05T20:41:20.422Z",
"modifier": "arossel",
"rev": "_h6SHyk---N"
},
{
"entContent": {
"approvedOn": "2023-05-09T17:25:23.860Z",
"description": "",
"hideFlag": false,
"legacyFullySuperseded": true,
"namespace": "GN037",
"releaseNotes": "Modification to the combining criteria such that one Benign Strong reaches Likely Benign (in the absence of conflicting evidence).",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:36.966Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-05-09T13:25:24.952Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-01T12:01:42.805Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2022-11-04T16:31:30.362Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-09T16:51:27.074Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "arossel",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-05-09T17:25:23.860Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "arossel",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-02-09T19:15:05.530Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"037"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0",
"version": "4.0.0",
"versioned": true
},
"entId": "GN037",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "037_PP1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",
"label": "PP1",
"ns": "037",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n* ≥5 informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 3-4 informative meiosis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n* 2 informative meiosis.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266904",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--C"
},
{
"entContent": {
"_uniqueProp": "037_PM6_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Because of the very high de novo rate of pathogenic variants in _UBE3A_, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PM6",
"ns": "037",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* ≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo without confirmation of paternity and maternity.\n\n* 1 occurrence of PM6.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266898",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266898",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxo2--O"
},
{
"entContent": {
"_uniqueProp": "037_BA1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoff is based on summation of prevalence of genes covered in the Rett/Angelman-like working group. The prevalence values were determined using the most conservative numbers found in the literature.",
"label": "BA1",
"ns": "037",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266892",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266892",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--E"
},
{
"entContent": {
"_uniqueProp": "037_PS4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "* Detailed phenotype not needed. Need to confirm patient is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.\n* Patient can be published OR an internal case OR observed at an outside lab (i.e. via ClinVar) OR described in the reputable databases (LOVD). However, the independent case has to be confirmed to be a different patient than yours (compare gender/age).\n* Do not use this criterion for variants where BS1 is applied or where PM2 does not apply.",
"label": "PS4",
"ns": "037",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266890",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266890",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--C"
},
{
"entContent": {
"_uniqueProp": "037_BS3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "037",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.\n\n* RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.\n* Not applicable for other functional studies (see tables for other accepted functional studies).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266885",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266885",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxp---N"
},
{
"entContent": {
"_uniqueProp": "037_BP5_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "* For example if a variant in _UBE3A_ is identified in a patient with lissencephaly in whom a pathogenic variant is identified in the _PAFAH1B1_ gene.\n* Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.\n* Do not apply if variant is de novo.",
"label": "BP5",
"ns": "037",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* ≥3 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.\n\n* 1-2 cases with alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266906",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266906",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpC--_"
},
{
"entContent": {
"_uniqueProp": "037_BP3_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "037",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266901",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266901",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--H"
},
{
"entContent": {
"_uniqueProp": "037_BS2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "- Should be applied in cases where the healthy adult is devoid of neurodevelopmental phenotypes. \n- Best to use with internal curated data that includes clinical information or published patients that have been phenotyped.",
"label": "BS2",
"ns": "037",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 4 unaffected (related and maternally inherited or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in the heterozygous/hemizygous state in a healthy adult.\n\n* 2 unaffected (related and maternally inherited or unrelated) heterozygotes",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266884",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266884",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxo2--L"
},
{
"entContent": {
"_uniqueProp": "037_PP4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "037",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266883",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266883",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxp---M"
},
{
"entContent": {
"_uniqueProp": "037_PP5_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "037",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266908",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266908",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--J"
},
{
"entContent": {
"_uniqueProp": "037_PVS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "For intragenic deletions/duplications that are predicted to result in a product that preserves reading frame:\n\n* For single exon in-frame deletions assign the same strength (PVS1, PVS1\\_strong, or PVS1\\_moderate) as for splice site variants that preserve reading frame indicated above.\n* For multiple exon in-frame deletions PVS1 can be assigned to deletions that include single in-frame exons in the PVS1 category listed in the splice site section above OR if the exon contains a functionally important domain as specified in PM1.\n* Given the extensive data available for _UBE3A_, classifications for single or multi-exon in-frame deletions are assigned as PVS1 or PVS1\\_strong. Refer to PVS1 flow chart for additional guidance.",
"label": "PVS1",
"ns": "037",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n\n* Use as defined by ClinGen SVI working group (PMID:30192042).\n* PVS1 is applicable for any truncating variant up to p.K841[5](#PMID_9887341), for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where loss of function is a known mechanism of disease.\n* PVS1_Moderate is applicable for any truncating variant distal of p.G850.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266905",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--D"
},
{
"entContent": {
"_uniqueProp": "037_PM4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM4",
"ns": "037",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein length changes due to stop-loss variants.\n\n* PM4\\_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals.[9](#PMID_25212744)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.\n\n* Smaller in-frame events (\\< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266895",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxo2--N"
},
{
"entContent": {
"_uniqueProp": "037_PS2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable to all genes in affected individuals identified as mosaic for the variant (as the presence of a variant in the mosaic state is confirmatory of the variant being de novo). \n\nBecause of the very high de novo rate of pathogenic variants in UBE3A, de novo observation can be attributed the highest value points per proband (2 points for confirmed de novo and 1 point for assumed de novo) if the patient is known to be affected with a neurodevelopmental phenotype consistent with the gene.",
"label": "PS2",
"ns": "037",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* ≥2 independent occurrences of PS2.\n* ≥2 independent occurrences of PM6 and one occurrence of PS2.\n* Evidence from literature must be fully evaluated to support independent events.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\n\n* 1 occurrence of PS2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "004",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266891",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266891",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--_"
},
{
"entContent": {
"_uniqueProp": "037_PP2_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "037",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266888",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266888",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxp---O"
},
{
"entContent": {
"_uniqueProp": "037_PM1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "037",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Located in a mutational hot spot and/or critical and well-established functional domain.\n\n* 3’ cysteine binding site: aa 820[5](#PMID_9887341)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266887",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266887",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxo2--M"
},
{
"entContent": {
"_uniqueProp": "037_BP7_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "For silent variants BP4 and BP7 can be added.",
"label": "BP7",
"ns": "037",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.\n* Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266909",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266909",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--E"
},
{
"entContent": {
"_uniqueProp": "037_BP4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "037",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* For missense variants use REVEL with a score ≤ 0.15.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266903",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266903",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpK--_"
},
{
"entContent": {
"_uniqueProp": "037_BP2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Knock out of _UBE3A_ results in disease but viable phenotype.[7](#PMID_9808466)",
"label": "BP2",
"ns": "037",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.\n\n* BP2 is not applicable for UBE3A _in trans_ state.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266900",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266900",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--A"
},
{
"entContent": {
"_uniqueProp": "037_PS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "037",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266899",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266899",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpC---"
},
{
"entContent": {
"_uniqueProp": "037_BS4_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",
"label": "BS4",
"ns": "037",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [
"Strength"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member, when seen in two or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family.\n\n* Absent in a similarly affected family member.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266897",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--G"
},
{
"entContent": {
"_uniqueProp": "037_BS1_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "The frequency cutoffs are based on MECP2 expected disease allele frequency (1 in 8500 females/1.5 alleles [assumes 50/50 male/female ratio]). MECP2 is the most prevalent of the genes covered in the Rett/Angelman-like working group and was chosen as most conservative number.",
"label": "BS1",
"ns": "037",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "* Use large population databases (i.e. gnomAD).\n* Use if variant is present at ≥0.00008 (0.008%) and \\<0.0003 (0.03%) in any sub-population.\n* Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266894",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266894",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--F"
},
{
"entContent": {
"_uniqueProp": "037_PP3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "037",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.\n\n* For missense variants use REVEL with a score ≥ 0.75.\n* For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266889",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266889",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe---"
},
{
"entContent": {
"_uniqueProp": "037_PM2_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "037",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266882",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266882",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpG--J"
},
{
"entContent": {
"_uniqueProp": "037_BP6_nuclear_UBE3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "037",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266907",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266907",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpW--I"
},
{
"entContent": {
"_uniqueProp": "037_PS3_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "037",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [
"Disease"
],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.\n* Do not use for canonical splice site variants and when PVS1 is used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect.\n\n* RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).\n* See included table for acceptable functional studies.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266902",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266902",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpe--B"
},
{
"entContent": {
"_uniqueProp": "037_BP1_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "037",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266896",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxp---P"
},
{
"entContent": {
"_uniqueProp": "037_PM3_nuclear_UBE3A",
"additionalComments": "Not applicable for UBE3A.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "037",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266893",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266893",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpK---"
},
{
"entContent": {
"_uniqueProp": "037_PM5_nuclear_UBE3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"UBE3A"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "037",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n* ≥2 different missense changes affecting the amino acid residue.\n* Do not apply PM1 in these situations.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\n\n* A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533266886",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533266886",
"modified": "2023-05-09T17:25:24.380Z",
"modifier": "arossel",
"rev": "_h6SHxpG--K"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0007113",
"lbl": "Angelman syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3941"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0007113"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/angelman_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005027"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019040"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10049004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1106558408"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/58144"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C531619"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D017204"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/76880004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0162635"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/Q93.51"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_1932"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C75462"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_72"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/105830"
}
],
"definition": {
"val": "A neurogenetic disorder characterized by severe intellectual deficit and distinct facial dysmorphic features.",
"xrefs": [
"Orphanet:72",
"https://orcid.org/0000-0001-5208-3432"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Angelman syndrome",
"xrefs": [
"DOID:1932",
"ICD10CM:Q93.51",
"MONDO:Lexical",
"NCIT:C75462",
"OMIM:105830",
"Orphanet:72",
"icd11.foundation:1106558408"
]
},
{
"pred": "hasExactSynonym",
"val": "Angelman’s syndrome",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome",
"xrefs": [
"DOID:1932"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "puppetlike syndrome",
"xrefs": [
"DOID:1932"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Angelman syndrome (Type 1)",
"xrefs": [
"DECIPHER:4"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Angelman syndrome (Type 2)",
"xrefs": [
"DECIPHER:54"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "AS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Angelman syndrome chromosome region"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome (formerly)",
"xrefs": [
"GARD:0005810"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#DEPRECATED",
"val": "happy puppet syndrome, formerly"
}
],
"xrefs": [
{
"val": "DECIPHER:4"
},
{
"val": "DECIPHER:54"
},
{
"val": "DOID:1932"
},
{
"val": "GARD:5810"
},
{
"val": "ICD10CM:Q93.51"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:58144"
},
{
"val": "MESH:C531619"
},
{
"val": "MESH:D017204"
},
{
"val": "MedDRA:10049004"
},
{
"val": "NANDO:1200686"
},
{
"val": "NANDO:2200960"
},
{
"val": "NCIT:C75462"
},
{
"val": "NORD:782"
},
{
"val": "OMIM:105830"
},
{
"val": "Orphanet:72"
},
{
"val": "SCTID:76880004"
},
{
"val": "UMLS:C0162635"
},
{
"val": "icd11.foundation:1106558408"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0007113",
"name": "Angelman syndrome"
},
"entId": "MONDO:0007113",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0007113",
"entType": "Disease",
"ldhId": "135642213",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642213",
"modified": "2025-10-07T15:43:23.289Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7VarW---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056966728384500,
"agr": "HGNC:12496",
"alias_name": [
"Angelman syndrome"
],
"alias_symbol": [
"AS",
"ANCR",
"E6-AP",
"FLJ26981"
],
"ccds_id": [
"CCDS45192",
"CCDS86436",
"CCDS32177",
"CCDS45191"
],
"date_approved_reserved": "1993-10-21",
"date_modified": "2021-05-26",
"date_name_changed": "2008-07-31",
"ena": [
"AF002224"
],
"ensembl_gene_id": "ENSG00000114062",
"entrez_id": "7337",
"enzyme_id": [
"2.3.2.26"
],
"gene_group": [
"HECT domain containing"
],
"gene_group_id": [
1959
],
"hgnc_id": "HGNC:12496",
"location": "15q11.2",
"location_sortable": "15q11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"NGRL, Manchester LOVD|http://ngrl.manchester.ac.uk/LOVDv.2.0/home.php?select_db=UBE3A",
"LRG_15|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_15.xml"
],
"mane_select": [
"ENST00000648336.2",
"NM_130839.5"
],
"mgd_id": [
"MGI:105098"
],
"name": "ubiquitin protein ligase E3A",
"omim_id": [
"601623"
],
"orphanet": 120365,
"prev_name": [
"human papilloma virus E6-associated protein"
],
"prev_symbol": [
"EPVE6AP",
"HPVE6A"
],
"pubmed_id": [
8221889
],
"refseq_accession": [
"NM_000462"
],
"rgd_id": [
"RGD:1306361"
],
"status": "Approved",
"symbol": "UBE3A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc059gvn.1",
"uniprot_ids": [
"Q05086"
],
"uuid": "dce8245d-bf9e-41fa-b4f2-e2a570703193",
"vega_id": "OTTHUMG00000171548"
},
"NCBI": {
"id": "7337"
}
},
"entId": "UBE3A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12496",
"entType": "Gene",
"ldhId": "135641941",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641941",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---H"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "037_nuclear_UBE3A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0007113",
"preferredTitle": "Angelman syndrome"
}
],
"gene": "UBE3A",
"preferredTranscript": "NM_130838.2"
}
],
"ns": "037",
"references": [
{
"auths": [
"Bienvenu T",
"Carrié A",
"et al."
],
"doiStr": "10.1093/hmg/9.9.1377",
"id": "10814719",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1377-84.",
"source": "Hum Mol Genet",
"title": "MECP2 mutations account for most cases of typical forms of Rett syndrome.",
"vol": "9",
"year": "2000"
},
{
"auths": [
"Erlandson A",
"Hallberg B",
"et al."
],
"doiStr": "10.1007/s007870170034",
"id": "11469283",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 117-21.",
"source": "Eur Child Adolesc Psychiatry",
"title": "MECP2 mutation screening in Swedish classical Rett syndrome females.",
"vol": "10",
"year": "2001"
},
{
"auths": [
"Sadikovic B",
"Fernandes P",
"et al."
],
"doiStr": "10.1002/humu.22687",
"id": "25212744",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 1407-17.",
"source": "Hum Mutat",
"title": "Mutation Update for UBE3A variants in Angelman syndrome.",
"vol": "35",
"year": "2014"
},
{
"auths": [
"Fang P",
"Lev-Lehman E",
"et al."
],
"doiStr": "10.1093/hmg/8.1.129",
"id": "9887341",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 129-35.",
"source": "Hum Mol Genet",
"title": "The spectrum of mutations in UBE3A causing Angelman syndrome.",
"vol": "8",
"year": "1999"
},
{
"auths": [
"Fang P",
"Lev-Lehman E",
"et al."
],
"doiStr": "10.1093/hmg/8.1.129",
"id": "9887341",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 129-35.",
"source": "Hum Mol Genet",
"title": "The spectrum of mutations in UBE3A causing Angelman syndrome.",
"vol": "8",
"year": "1999"
},
{
"auths": [
"Sadikovic B",
"Fernandes P",
"et al."
],
"doiStr": "10.1002/humu.22687",
"id": "25212744",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 1407-17.",
"source": "Hum Mutat",
"title": "Mutation Update for UBE3A variants in Angelman syndrome.",
"vol": "35",
"year": "2014"
},
{
"auths": [
"Jiang YH",
"Armstrong D",
"et al."
],
"doiStr": "10.1016/s0896-6273(00)80596-6",
"id": "9808466",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. 799-811.",
"source": "Neuron",
"title": "Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.",
"vol": "21",
"year": "1998"
},
{
"auths": [
"Sadikovic B",
"Fernandes P",
"et al."
],
"doiStr": "10.1002/humu.22687",
"id": "25212744",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 1407-17.",
"source": "Hum Mutat",
"title": "Mutation Update for UBE3A variants in Angelman syndrome.",
"vol": "35",
"year": "2014"
},
{
"auths": [
"Sadikovic B",
"Fernandes P",
"et al."
],
"doiStr": "10.1002/humu.22687",
"id": "25212744",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 1407-17.",
"source": "Hum Mutat",
"title": "Mutation Update for UBE3A variants in Angelman syndrome.",
"vol": "35",
"year": "2014"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP5_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM4_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==4",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM6_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243114",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243114",
"modified": "2023-05-09T17:25:24.295Z",
"modifier": "arossel",
"rev": "_h6SHyTW--x"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-04-18T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-23T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-11-27T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-02-17T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Rett and Angelman-like Disorders",
"shortBaseName": "Rett/AS",
"shortTitle": "Rett and Angelman-like Disorders VCEP",
"title": "Rett and Angelman-like Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50022",
"entIri": "http://clinicalgenome.org/affiliation/50022",
"entType": "Organization",
"ldhId": "135637643",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637643",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-12-31T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacy": true,
"legacyReplaced": true,
"namespace": "GN016",
"releaseNotes": "Modifications to PP3 and BP4 (in silico prediction criteria) that affect splice site prediction, including thresholds to use for splice site prediction in silico tools.",
"shortTitle": "Rett and Angelman-like Disorders Variant Interpretation Guidelines",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7339/clingen_rettas_acmg_specifications_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-12-31T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"016"
],
"title": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2",
"version": "2.0.0",
"versioned": true
},
"entId": "GN016",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637589",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589",
"modified": "2023-09-29T15:16:47.877Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--_"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243107",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243107",
"modified": "2023-09-29T15:16:49.726Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--W"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN038",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:41.717Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:17:40.158Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:16:53.504Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:13.401Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:10.967Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"038"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN038",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962873819100,
"agr": "HGNC:15454",
"alias_symbol": [
"KIAA0862",
"SOC2",
"SUR-8",
"SOC-2",
"SUR8"
],
"ccds_id": [
"CCDS7568",
"CCDS58095"
],
"date_approved_reserved": "2001-03-30",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ena": [
"AB020669"
],
"ensembl_gene_id": "ENSG00000108061",
"entrez_id": "8036",
"gene_group": [
"MicroRNA protein coding host genes"
],
"gene_group_id": [
1691
],
"hgnc_id": "HGNC:15454",
"location": "10q25.2",
"location_sortable": "10q25.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_753|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_753.xml"
],
"mane_select": [
"ENST00000369452.9",
"NM_007373.4"
],
"mgd_id": [
"MGI:1927197"
],
"name": "SHOC2 leucine rich repeat scaffold protein",
"omim_id": [
"602775"
],
"orphanet": 220877,
"prev_name": [
"soc-2 (suppressor of clear, C.elegans) homolog",
"soc-2 suppressor of clear homolog (C. elegans)",
"SHOC2 leucine-rich repeat scaffold protein",
"SHOC2, leucine rich repeat scaffold protein"
],
"pubmed_id": [
9618511,
9674433,
10783161
],
"refseq_accession": [
"NM_007373"
],
"rgd_id": [
"RGD:1308146"
],
"status": "Approved",
"symbol": "SHOC2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001kzl.5",
"uniprot_ids": [
"Q9UQ13"
],
"uuid": "9ee464ec-a210-4c21-9ac1-10b8023c489b",
"vega_id": "OTTHUMG00000019047"
},
"NCBI": {
"id": "8036"
}
},
"entId": "SHOC2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:15454",
"entType": "Gene",
"ldhId": "135641811",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641811",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--G"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "038_nuclear_SHOC2",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "SHOC2"
}
],
"ns": "038",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243115",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243115",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--F"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243108",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243108",
"modified": "2023-09-06T21:11:11.189Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--H"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN039",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:45.478Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:16:28.104Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:15:00.296Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:12:39.958Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:27.125Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"039"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN039",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955918614500,
"agr": "HGNC:7989",
"alias_symbol": [
"N-ras"
],
"ccds_id": [
"CCDS877"
],
"cosmic": "NRAS",
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2017-02-27",
"ena": [
"BC005219"
],
"ensembl_gene_id": "ENSG00000213281",
"entrez_id": "4893",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:7989",
"iuphar": "objectId:2823",
"location": "1p13.2",
"location_sortable": "01p13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"NRASbase: Mutation registry for autoimmune lymphoproliferative syndrome type IV|http://structure.bmc.lu.se/idbase/NRASbase/",
"LRG_92|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_92.xml"
],
"mane_select": [
"ENST00000369535.5",
"NM_002524.5"
],
"mgd_id": [
"MGI:97376"
],
"name": "NRAS proto-oncogene, GTPase",
"omim_id": [
"164790"
],
"orphanet": 221346,
"prev_name": [
"neuroblastoma RAS viral (v-ras) oncogene homolog",
"neuroblastoma RAS viral oncogene homolog"
],
"pubmed_id": [
6705568,
11524732
],
"refseq_accession": [
"NM_002524"
],
"rgd_id": [
"RGD:3205"
],
"status": "Approved",
"symbol": "NRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc009wgu.4",
"uniprot_ids": [
"P01111"
],
"uuid": "50dccc85-0457-43d2-8c89-b4014ec96185",
"vega_id": "OTTHUMG00000012059"
},
"NCBI": {
"id": "4893"
}
},
"entId": "NRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7989",
"entType": "Gene",
"ldhId": "135641812",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641812",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "039_nuclear_NRAS",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "NRAS"
}
],
"ns": "039",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243116",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243116",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW-_W"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
}
]
},
"ldhId": "643243109",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243109",
"modified": "2023-09-06T21:11:27.252Z",
"modifier": "sharriso",
"rev": "_h6SHykG--D"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN040",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:49.407Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:33:42.890Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:31:56.497Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:38.972Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:39.602Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"040"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN040",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056958857773000,
"agr": "HGNC:9829",
"alias_name": [
"C-Raf proto-oncogene, serine/threonine kinase"
],
"alias_symbol": [
"Raf-1",
"c-Raf",
"CRAF"
],
"ccds_id": [
"CCDS87047",
"CCDS2612"
],
"cosmic": "RAF1",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-04-13",
"date_name_changed": "2014-06-26",
"ena": [
"X03484"
],
"ensembl_gene_id": "ENSG00000132155",
"entrez_id": "5894",
"gene_group": [
"Mitogen-activated protein kinase kinase kinases",
"RAF family"
],
"gene_group_id": [
654,
1157
],
"hgnc_id": "HGNC:9829",
"iuphar": "objectId:2184",
"location": "3p25.2",
"location_sortable": "03p25.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_413|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_413.xml"
],
"mane_select": [
"ENST00000442415.7",
"NM_001354689.3"
],
"mgd_id": [
"MGI:97847"
],
"name": "Raf-1 proto-oncogene, serine/threonine kinase",
"omim_id": [
"164760"
],
"orphanet": 138722,
"prev_name": [
"v-raf-1 murine leukemia viral oncogene homolog 1"
],
"pubmed_id": [
1611909
],
"refseq_accession": [
"NM_002880"
],
"rgd_id": [
"RGD:3531"
],
"status": "Approved",
"symbol": "RAF1",
"ucsc_id": "uc003bxf.5",
"uniprot_ids": [
"P04049"
],
"uuid": "b38560c9-a1b1-4bbd-a005-376c7eaca0b3",
"vega_id": "OTTHUMG00000129789"
},
"NCBI": {
"id": "5894"
}
},
"entId": "RAF1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9829",
"entType": "Gene",
"ldhId": "135641813",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641813",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "040_nuclear_RAF1",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "RAF1"
}
],
"ns": "040",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243117",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243117",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW-_X"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243110",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243110",
"modified": "2023-09-06T21:11:39.749Z",
"modifier": "sharriso",
"rev": "_h6SHykS--G"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN041",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:53.367Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:35:43.611Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:34:23.894Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:47:58.212Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:11:50.393Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"041"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN041",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963944415200,
"agr": "HGNC:11187",
"alias_symbol": [
"HGF",
"GF1"
],
"ccds_id": [
"CCDS1802"
],
"curator_notes": [
"There is no relationship between this gene and the plant ‘salt overly sensitive’ gene with the same symbol."
],
"date_approved_reserved": "1993-10-27",
"date_modified": "2021-04-13",
"date_name_changed": "2015-11-10",
"ena": [
"L13857"
],
"ensembl_gene_id": "ENSG00000115904",
"entrez_id": "6654",
"gene_group": [
"Pleckstrin homology domain containing",
"Dbl family Rho GEFs"
],
"gene_group_id": [
682,
722
],
"hgnc_id": "HGNC:11187",
"iuphar": "objectId:3096",
"location": "2p22.1",
"location_sortable": "02p22.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_754|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_754.xml"
],
"mane_select": [
"ENST00000402219.8",
"NM_005633.4"
],
"mgd_id": [
"MGI:98354"
],
"name": "SOS Ras/Rac guanine nucleotide exchange factor 1",
"omim_id": [
"182530"
],
"orphanet": 119781,
"prev_name": [
"gingival fibromatosis, hereditary, 1",
"son of sevenless homolog 1 (Drosophila)"
],
"prev_symbol": [
"GINGF"
],
"pubmed_id": [
8276400,
10995566
],
"refseq_accession": [
"NM_005633"
],
"rgd_id": [
"RGD:1310949"
],
"status": "Approved",
"symbol": "SOS1",
"ucsc_id": "uc061ikm.1",
"uniprot_ids": [
"Q07889"
],
"uuid": "403c9348-75fb-4105-b6ef-45a6bb741b36",
"vega_id": "OTTHUMG00000102109"
},
"NCBI": {
"id": "6654"
}
},
"entId": "SOS1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11187",
"entType": "Gene",
"ldhId": "135641814",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641814",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---G"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "041_nuclear_SOS1",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "SOS1"
}
],
"ns": "041",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243118",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243118",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTa---"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243111",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243111",
"modified": "2023-09-06T21:11:50.611Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN042",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:12:57.208Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:38:42.348Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:37:09.802Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:12.917Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:00.498Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"042"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN042",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963946512400,
"agr": "HGNC:11188",
"ccds_id": [
"CCDS9697"
],
"curator_notes": [
"There is no relationship between this gene and the plant ‘salt overly sensitive’ gene with the same symbol."
],
"date_approved_reserved": "1993-10-27",
"date_modified": "2016-10-05",
"date_name_changed": "2015-11-10",
"ena": [
"L13858"
],
"ensembl_gene_id": "ENSG00000100485",
"entrez_id": "6655",
"gene_group": [
"Pleckstrin homology domain containing",
"Dbl family Rho GEFs"
],
"gene_group_id": [
682,
722
],
"hgnc_id": "HGNC:11188",
"location": "14q21.3",
"location_sortable": "14q21.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000216373.10",
"NM_006939.4"
],
"mgd_id": [
"MGI:98355"
],
"name": "SOS Ras/Rho guanine nucleotide exchange factor 2",
"omim_id": [
"601247"
],
"orphanet": 434401,
"prev_name": [
"son of sevenless (Drosophilia) homolog 2",
"son of sevenless homolog 2 (Drosophila)"
],
"pubmed_id": [
8276400
],
"refseq_accession": [
"NM_006939"
],
"rgd_id": [
"RGD:620435"
],
"status": "Approved",
"symbol": "SOS2",
"ucsc_id": "uc001wxs.5",
"uniprot_ids": [
"Q07890"
],
"uuid": "00e6fd97-e609-4db9-8c21-ad4c9da431c6",
"vega_id": "OTTHUMG00000140292"
},
"NCBI": {
"id": "6655"
}
},
"entId": "SOS2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11188",
"entType": "Gene",
"ldhId": "135641815",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641815",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "042_nuclear_SOS2",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "SOS2"
}
],
"ns": "042",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243119",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243119",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW-_Z"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
}
]
},
"ldhId": "643243112",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243112",
"modified": "2023-09-06T21:12:00.626Z",
"modifier": "sharriso",
"rev": "_h6SHykG--S"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN043",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:01.042Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:41:50.919Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:39:57.331Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:18.623Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:09.143Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"043"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN043",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056958617649200,
"agr": "HGNC:9644",
"alias_name": [
"SH2 domain-containing protein tyrosine phosphatase 2"
],
"alias_symbol": [
"BPTP3",
"SH-PTP2",
"SHP-2",
"PTP2C",
"SHP2"
],
"ccds_id": [
"CCDS9163",
"CCDS81741",
"CCDS58280"
],
"cosmic": "PTPN11",
"date_approved_reserved": "1993-03-03",
"date_modified": "2021-05-26",
"date_name_changed": "2019-02-14",
"ena": [
"D13540"
],
"ensembl_gene_id": "ENSG00000179295",
"entrez_id": "5781",
"gene_group": [
"SH2 domain containing",
"Protein tyrosine phosphatases non-receptor type"
],
"gene_group_id": [
741,
812
],
"hgnc_id": "HGNC:9644",
"location": "12q24.13",
"location_sortable": "12q24.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_614|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_614.xml"
],
"mane_select": [
"ENST00000351677.7",
"NM_002834.5"
],
"mgd_id": [
"MGI:99511"
],
"name": "protein tyrosine phosphatase non-receptor type 11",
"omim_id": [
"176876"
],
"orphanet": 118143,
"prev_name": [
"Noonan syndrome 1",
"protein tyrosine phosphatase, non-receptor type 11"
],
"prev_symbol": [
"NS1"
],
"pubmed_id": [
7894486,
1280823
],
"refseq_accession": [
"NM_001330437"
],
"rgd_id": [
"RGD:3447"
],
"status": "Approved",
"symbol": "PTPN11",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001ttx.4",
"uniprot_ids": [
"Q06124"
],
"uuid": "3598f5ec-29fc-495b-a74a-9a05a111ab30",
"vega_id": "OTTHUMG00000134334"
},
"NCBI": {
"id": "5781"
}
},
"entId": "PTPN11",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9644",
"entType": "Gene",
"ldhId": "135641816",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641816",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "043_nuclear_PTPN11",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "PTPN11"
}
],
"ns": "043",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243120",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243120",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--O"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243113",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243113",
"modified": "2023-09-06T21:12:09.271Z",
"modifier": "sharriso",
"rev": "_h6SHykG--E"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN044",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:04.995Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:47:09.101Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:45:31.721Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:48:38.616Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:17.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"044"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN044",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056950878109700,
"agr": "HGNC:6407",
"alias_symbol": [
"KRAS1",
"K-Ras4B"
],
"ccds_id": [
"CCDS8703",
"CCDS8702"
],
"cosmic": "KRAS",
"date_approved_reserved": "1988-06-02",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-10",
"date_symbol_changed": "2005-01-24",
"ena": [
"BC010502"
],
"ensembl_gene_id": "ENSG00000133703",
"entrez_id": "3845",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:6407",
"iuphar": "objectId:2824",
"location": "12p12.1",
"location_sortable": "12p12.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_344|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_344.xml"
],
"mane_select": [
"ENST00000311936.8",
"NM_004985.5"
],
"mgd_id": [
"MGI:96680"
],
"name": "KRAS proto-oncogene, GTPase",
"omim_id": [
"190070"
],
"orphanet": 122879,
"prev_name": [
"v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog",
"v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog",
"Kirsten rat sarcoma viral oncogene homolog"
],
"prev_symbol": [
"KRAS2"
],
"refseq_accession": [
"NM_033360"
],
"rgd_id": [
"RGD:2981"
],
"status": "Approved",
"symbol": "KRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001rgp.3",
"uniprot_ids": [
"P01116"
],
"uuid": "b433a2e9-c3eb-451d-a0cd-0c88f1d6935f",
"vega_id": "OTTHUMG00000171193"
},
"NCBI": {
"id": "3845"
}
},
"entId": "KRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6407",
"entType": "Gene",
"ldhId": "135641817",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641817",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "044_nuclear_KRAS",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "KRAS"
}
],
"ns": "044",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243121",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243121",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--k"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
}
]
},
"ldhId": "643243114",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243114",
"modified": "2023-09-06T21:12:18.143Z",
"modifier": "sharriso",
"rev": "_h6SHykS--H"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN045",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:08.948Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:49:05.328Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:47:46.078Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:51:04.757Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:27.247Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"045"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN045",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056952807489500,
"agr": "HGNC:6840",
"alias_symbol": [
"MEK1",
"MAPKK1"
],
"ccds_id": [
"CCDS10216"
],
"cosmic": "MAP2K1",
"date_approved_reserved": "1993-11-05",
"date_modified": "2021-04-13",
"ena": [
"L11284"
],
"ensembl_gene_id": "ENSG00000169032",
"entrez_id": "5604",
"enzyme_id": [
"2.7.12.2"
],
"gene_group": [
"Mitogen-activated protein kinase kinases"
],
"gene_group_id": [
653
],
"hgnc_id": "HGNC:6840",
"iuphar": "objectId:2062",
"location": "15q22.31",
"location_sortable": "15q22.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"The Globin Gene Server|http://lovd.bx.psu.edu/home.php?select_db=MAP2K1",
"LRG_725|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_725.xml"
],
"mane_select": [
"ENST00000307102.10",
"NM_002755.4"
],
"mgd_id": [
"MGI:1346866"
],
"name": "mitogen-activated protein kinase kinase 1",
"omim_id": [
"176872"
],
"orphanet": 123135,
"prev_symbol": [
"PRKMK1"
],
"pubmed_id": [
9465908,
8388392
],
"refseq_accession": [
"NM_002755"
],
"rgd_id": [
"RGD:70495"
],
"status": "Approved",
"symbol": "MAP2K1",
"ucsc_id": "uc010bhq.4",
"uniprot_ids": [
"Q02750"
],
"uuid": "dbe1a6fc-0d4c-48a2-9a8f-b66f89a4bd4e",
"vega_id": "OTTHUMG00000133196"
},
"NCBI": {
"id": "5604"
}
},
"entId": "MAP2K1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6840",
"entType": "Gene",
"ldhId": "135641818",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641818",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "045_nuclear_MAP2K1",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "MAP2K1"
}
],
"ns": "045",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243122",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243122",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--m"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243115",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243115",
"modified": "2023-09-06T21:12:27.379Z",
"modifier": "sharriso",
"rev": "_h6SHykG--F"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN046",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:12.804Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:27:14.680Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:25:24.102Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:50:36.608Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:35.383Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"046"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN046",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949589409800,
"agr": "HGNC:5173",
"ccds_id": [
"CCDS7698",
"CCDS7699"
],
"cosmic": "HRAS",
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2016-06-10",
"ena": [
"AJ437024"
],
"ensembl_gene_id": "ENSG00000174775",
"entrez_id": "3265",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:5173",
"iuphar": "objectId:2822",
"location": "11p15.5",
"location_sortable": "11p15.5",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_506|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_506.xml"
],
"mane_select": [
"ENST00000311189.8",
"NM_005343.4"
],
"mgd_id": [
"MGI:96224"
],
"name": "HRas proto-oncogene, GTPase",
"omim_id": [
"190020"
],
"orphanet": 122499,
"prev_name": [
"v-Ha-ras Harvey rat sarcoma viral oncogene homolog",
"Harvey rat sarcoma viral oncogene homolog"
],
"prev_symbol": [
"HRAS1"
],
"refseq_accession": [
"NM_176795"
],
"rgd_id": [
"RGD:2827"
],
"status": "Approved",
"symbol": "HRAS",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc010qvx.3",
"uniprot_ids": [
"P01112"
],
"uuid": "5e0f7545-006b-46cf-b1dd-1b96b73c88d3",
"vega_id": "OTTHUMG00000131919"
},
"NCBI": {
"id": "3265"
}
},
"entId": "HRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5173",
"entType": "Gene",
"ldhId": "135641819",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641819",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "046_nuclear_HRAS",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "HRAS"
}
],
"ns": "046",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243123",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243123",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--P"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243116",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243116",
"modified": "2023-09-06T21:12:35.517Z",
"modifier": "sharriso",
"rev": "_h6SHykS--I"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN047",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:16.731Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-08T14:29:35.249Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-08T14:27:46.530Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T18:13:33.042Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:43.388Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"047"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN047",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056959328583700,
"agr": "HGNC:10023",
"alias_name": [
"Ric-like, expressed in many tissues",
"GTP-binding protein Roc1"
],
"alias_symbol": [
"RIBB",
"ROC1",
"MGC125864",
"MGC125865"
],
"ccds_id": [
"CCDS58037",
"CCDS1123",
"CCDS58036"
],
"date_approved_reserved": "1996-08-28",
"date_modified": "2021-04-13",
"date_name_changed": "2016-05-04",
"date_symbol_changed": "2002-09-13",
"ena": [
"AF084462"
],
"ensembl_gene_id": "ENSG00000143622",
"entrez_id": "6016",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:10023",
"location": "1q22",
"location_sortable": "01q22",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1372|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1372.xml"
],
"mane_select": [
"ENST00000368323.8",
"NM_006912.6"
],
"mgd_id": [
"MGI:108053"
],
"name": "Ras like without CAAX 1",
"omim_id": [
"609591"
],
"orphanet": 358630,
"prev_name": [
"Ric (Drosophila)-like, expressed in many tissues"
],
"prev_symbol": [
"RIT"
],
"pubmed_id": [
8824319,
8918462
],
"refseq_accession": [
"NM_006912"
],
"rgd_id": [
"RGD:1559874"
],
"status": "Approved",
"symbol": "RIT1",
"ucsc_id": "uc001fmh.3",
"uniprot_ids": [
"Q92963"
],
"uuid": "43b6b6f9-9c5d-4df6-ba5e-a347f30ab080",
"vega_id": "OTTHUMG00000014104"
},
"NCBI": {
"id": "6016"
}
},
"entId": "RIT1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10023",
"entType": "Gene",
"ldhId": "135641820",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641820",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "047_nuclear_RIT1",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "RIT1"
}
],
"ns": "047",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243124",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243124",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--R"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
}
]
},
"ldhId": "643243117",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243117",
"modified": "2023-09-06T21:12:43.520Z",
"modifier": "sharriso",
"rev": "_h6SHykS--J"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN048",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:20.429Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:50:54.076Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:49:40.294Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:30.196Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:12:53.839Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"048"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN048",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056952808538000,
"agr": "HGNC:6842",
"alias_symbol": [
"MEK2"
],
"ccds_id": [
"CCDS12120"
],
"cosmic": "MAP2K2",
"date_approved_reserved": "1993-11-05",
"date_modified": "2021-04-13",
"ena": [
"L11285"
],
"ensembl_gene_id": "ENSG00000126934",
"entrez_id": "5605",
"enzyme_id": [
"2.7.12.2"
],
"gene_group": [
"Mitogen-activated protein kinase kinases"
],
"gene_group_id": [
653
],
"hgnc_id": "HGNC:6842",
"iuphar": "objectId:2063",
"location": "19p13.3",
"location_sortable": "19p13.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_750|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_750.xml"
],
"mane_select": [
"ENST00000262948.10",
"NM_030662.4"
],
"mgd_id": [
"MGI:1346867"
],
"name": "mitogen-activated protein kinase kinase 2",
"omim_id": [
"601263"
],
"orphanet": 123140,
"prev_symbol": [
"PRKMK2"
],
"pubmed_id": [
8388392
],
"refseq_accession": [
"NM_030662"
],
"rgd_id": [
"RGD:61888"
],
"status": "Approved",
"symbol": "MAP2K2",
"ucsc_id": "uc002lzk.4",
"uniprot_ids": [
"P36507"
],
"uuid": "52a104b3-3f62-4cb6-ad59-1fe0fbb432f2",
"vega_id": "OTTHUMG00000134286"
},
"NCBI": {
"id": "5605"
}
},
"entId": "MAP2K2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6842",
"entType": "Gene",
"ldhId": "135641821",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641821",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC---"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "048_nuclear_MAP2K2",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "MAP2K2"
}
],
"ns": "048",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243125",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243125",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--S"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
}
]
},
"ldhId": "643243118",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243118",
"modified": "2023-09-06T21:12:53.963Z",
"modifier": "sharriso",
"rev": "_h6SHykG--T"
},
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN049",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"releaseNotes": "",
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:24.322Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-07T18:18:54.826Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-07T18:18:12.960Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-moved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-moved",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-07-19T17:49:03.904Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:05.564Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"049"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN049",
"entType": "SequenceVariantInterpretation",
"ld": {
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056943387082800,
"agr": "HGNC:1097",
"alias_symbol": [
"BRAF1"
],
"ccds_id": [
"CCDS87555",
"CCDS5863"
],
"cosmic": "BRAF",
"date_approved_reserved": "1991-07-16",
"date_modified": "2021-05-26",
"date_name_changed": "2014-06-26",
"ena": [
"M95712"
],
"ensembl_gene_id": "ENSG00000157764",
"entrez_id": "673",
"gene_group": [
"Mitogen-activated protein kinase kinase kinases",
"RAF family"
],
"gene_group_id": [
654,
1157
],
"hgnc_id": "HGNC:1097",
"iuphar": "objectId:1943",
"location": "7q34",
"location_sortable": "07q34",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_299|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_299.xml"
],
"mane_select": [
"ENST00000644969.2",
"NM_001374258.1"
],
"mgd_id": [
"MGI:88190"
],
"name": "B-Raf proto-oncogene, serine/threonine kinase",
"omim_id": [
"164757"
],
"orphanet": 119066,
"prev_name": [
"v-raf murine sarcoma viral oncogene homolog B"
],
"pubmed_id": [
2284096,
1565476
],
"refseq_accession": [
"NM_004333"
],
"rgd_id": [
"RGD:619908"
],
"status": "Approved",
"symbol": "BRAF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003vwc.5",
"uniprot_ids": [
"P15056"
],
"uuid": "572c5ff2-c510-496c-a055-0342aaa6d9eb",
"vega_id": "OTTHUMG00000157457"
},
"NCBI": {
"id": "673"
}
},
"entId": "BRAF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1097",
"entType": "Gene",
"ldhId": "135641822",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641822",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyAy---"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "049_nuclear_BRAF",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "BRAF"
}
],
"ns": "049",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243126",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243126",
"modified": "2024-01-29T11:34:26.659Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--H"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2017-07-18T00:00:00.000Z",
"description": "ACMG rules for RASopathy",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN004",
"notes": "These criteria should only be used to classify germline variants potentially associated with a RASopathy phenotype. Please note that these adapted criteria are not currently designed to classify variants relative to non-RASopathy phenotypes (e.g. loss of function variants in PTPN11 related to metachondromatosis); however, information about these other genotype:phenotype correlations are noted within the supplemental material. These criteria are also not designed to classify somatic variation in these genes. It is well-known that information about known somatic mutations can be utilized as supporting evidence for classifying variants relative to the RASopathy spectrum disorders given the disease mechanisms are directly correlated. Future initiatives in conjunction with the ClinGen somatic working group will aim to define this relationship in subsequent versions of this documentation. Currently, specific phenotype:genotype correlations regarding somatic variants should not be used as evidence to support germline pathogenicity.",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29493581"
}
],
"shortTitle": "ACMG variant classification (RASopathy)",
"specificationSource": "https://www.clinicalgenome.org/docs/clingen-rasopathy-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2017-07-18T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"004"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1",
"version": "1.0.0"
},
"entId": "GN004",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637576",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637576",
"modified": "2023-09-29T15:16:45.247Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--H"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243119",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243119",
"modified": "2023-09-06T21:13:05.701Z",
"modifier": "sharriso",
"rev": "_h6SHykS--K"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN050",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:28.663Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"050"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN050",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6750"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1452641873"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/78754"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
}
],
"comments": [
"This term's classification was reviewed in the context of the Strategic Refinement project (2023) and was determined to be excluded from the 'nervous system disorder' (MONDO:0005071) ontology branch (https://orcid.org/0000-0001-9310-0163) and from the 'metabolic disease' (MONDO:0005066) ontology branch (https://orcid.org/0000-0002-1780-5230)"
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush"
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
}
],
"xrefs": [
{
"val": "DOID:0050439"
},
{
"val": "GARD:7843"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:78754"
},
{
"val": "MESH:D052245"
},
{
"val": "MedDRA:10063396"
},
{
"val": "NANDO:1200941"
},
{
"val": "NCIT:C85217"
},
{
"val": "NORD:1816"
},
{
"val": "OMIMPS:276900"
},
{
"val": "Orphanet:886"
},
{
"val": "UMLS:C0271097"
},
{
"val": "icd11.foundation:1452641873"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642100",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642100",
"modified": "2025-10-07T15:46:46.842Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Yhee---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056944316121000,
"agr": "HGNC:13733",
"alias_name": [
"cadherin-related family member 23"
],
"alias_symbol": [
"CDHR23"
],
"ccds_id": [
"CCDS81473",
"CCDS86100",
"CCDS44429",
"CCDS81472",
"CCDS73146",
"CCDS53540"
],
"date_approved_reserved": "2000-10-19",
"date_modified": "2021-05-26",
"date_name_changed": "2016-06-03",
"ena": [
"AY010111"
],
"ensembl_gene_id": "ENSG00000107736",
"entrez_id": "64072",
"gene_group": [
"Cadherin related",
"MicroRNA protein coding host genes"
],
"gene_group_id": [
24,
1691
],
"hgnc_id": "HGNC:13733",
"location": "10q22.1",
"location_sortable": "10q22.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org/",
"Mutations of the Cadherin-related Protein 23 Gene|http://www.retina-international.org/files/sci-news/cdh23mut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=CDH23"
],
"mane_select": [
"ENST00000224721.12",
"NM_022124.6"
],
"mgd_id": [
"MGI:1890219"
],
"name": "cadherin related 23",
"omim_id": [
"605516"
],
"orphanet": 119281,
"prev_name": [
"cadherin-like 23"
],
"prev_symbol": [
"DFNB12",
"USH1D"
],
"pubmed_id": [
11090341
],
"refseq_accession": [
"NM_052836"
],
"rgd_id": [
"RGD:619760"
],
"status": "Approved",
"symbol": "CDH23",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc057twh.2",
"uniprot_ids": [
"Q9H251"
],
"uuid": "dbeb8630-ed09-475e-a5b0-40e2a4a27c29",
"vega_id": "OTTHUMG00000019347"
},
"NCBI": {
"id": "64072"
}
},
"entId": "CDH23",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:13733",
"entType": "Gene",
"ldhId": "135641858",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641858",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyAy--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "050_nuclear_CDH23",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
},
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "CDH23",
"preferredTranscript": "NM_022124.6"
}
],
"ns": "050",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243127",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243127",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--e"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
}
]
},
"ldhId": "643243120",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243120",
"modified": "2022-08-18T19:13:32.244Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN051",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:32.682Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"051"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for COCH Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN051",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056944971481000,
"agr": "HGNC:2180",
"alias_symbol": [
"COCH-5B2"
],
"ccds_id": [
"CCDS9640",
"CCDS86382"
],
"date_approved_reserved": "1998-10-16",
"date_modified": "2021-05-26",
"date_name_changed": "2013-05-01",
"ensembl_gene_id": "ENSG00000100473",
"entrez_id": "1690",
"hgnc_id": "HGNC:2180",
"location": "14q12",
"location_sortable": "14q12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org"
],
"mane_select": [
"ENST00000396618.9",
"NM_004086.3"
],
"mgd_id": [
"MGI:1278313"
],
"name": "cochlin",
"omim_id": [
"603196"
],
"orphanet": 120681,
"prev_name": [
"coagulation factor C (Limulus polyphemus homolog); cochlin",
"coagulation factor C homolog, cochlin (Limulus polyphemus)"
],
"prev_symbol": [
"DFNA31",
"DFNA9"
],
"pubmed_id": [
9806553
],
"refseq_accession": [
"NM_004086"
],
"rgd_id": [
"RGD:1308536"
],
"status": "Approved",
"symbol": "COCH",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001wqr.3",
"uniprot_ids": [
"O43405"
],
"uuid": "a5e29779-7c29-46ca-8ca9-f65eaef96b2b",
"vega_id": "OTTHUMG00000029432"
},
"NCBI": {
"id": "1690"
}
},
"entId": "COCH",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:2180",
"entType": "Gene",
"ldhId": "135641857",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641857",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "051_nuclear_COCH",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "COCH",
"preferredTranscript": "NM_004086.3"
}
],
"ns": "051",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243128",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243128",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--f"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243121",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243121",
"modified": "2022-08-18T19:13:36.425Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN052",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:36.877Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"052"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GJB2 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN052",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948391936000,
"agr": "HGNC:4284",
"alias_name": [
"connexin 26"
],
"alias_symbol": [
"CX26",
"NSRD1"
],
"ccds_id": [
"CCDS9290"
],
"date_approved_reserved": "1990-02-12",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-09",
"ena": [
"M86849"
],
"ensembl_gene_id": "ENSG00000165474",
"entrez_id": "2706",
"gene_group": [
"Gap junction proteins"
],
"gene_group_id": [
314
],
"hgnc_id": "HGNC:4284",
"iuphar": "objectId:716",
"location": "13q12.11",
"location_sortable": "13q12.11",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"The Connexin-deafness homepage|http://davinci.crg.es/deafness/",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=GJB2",
"LRG_1350|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1350.xml"
],
"mane_select": [
"ENST00000382848.5",
"NM_004004.6"
],
"mgd_id": [
"MGI:95720"
],
"name": "gap junction protein beta 2",
"omim_id": [
"121011"
],
"orphanet": 122129,
"prev_name": [
"gap junction protein, beta 2, 26kD (connexin 26)",
"gap junction protein, beta 2, 26kDa (connexin 26)",
"gap junction protein, beta 2, 26kDa"
],
"prev_symbol": [
"DFNB1",
"DFNA3"
],
"pubmed_id": [
9139825
],
"refseq_accession": [
"NM_004004"
],
"rgd_id": [
"RGD:728891"
],
"status": "Approved",
"symbol": "GJB2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001umy.4",
"uniprot_ids": [
"P29033"
],
"uuid": "91fef4ae-bc30-4ba0-ace1-9a1f58fc5004",
"vega_id": "OTTHUMG00000016513"
},
"NCBI": {
"id": "2706"
}
},
"entId": "GJB2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4284",
"entType": "Gene",
"ldhId": "135641856",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641856",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2---"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "052_nuclear_GJB2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "GJB2",
"preferredTranscript": "NM_004004.6"
}
],
"ns": "052",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243129",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243129",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--O"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
}
]
},
"ldhId": "643243122",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243122",
"modified": "2022-08-18T19:13:40.396Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN053",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:40.836Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"053"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KCNQ4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN053",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056950627500000,
"agr": "HGNC:6298",
"alias_symbol": [
"Kv7.4"
],
"ccds_id": [
"CCDS456"
],
"date_approved_reserved": "1999-02-05",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-04",
"ena": [
"AF105202"
],
"ensembl_gene_id": "ENSG00000117013",
"entrez_id": "9132",
"gene_group": [
"Potassium voltage-gated channels"
],
"gene_group_id": [
274
],
"hgnc_id": "HGNC:6298",
"iuphar": "objectId:563",
"location": "1p34.2",
"location_sortable": "01p34.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1378|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1378.xml"
],
"mane_select": [
"ENST00000347132.10",
"NM_004700.4"
],
"mgd_id": [
"MGI:1926803"
],
"name": "potassium voltage-gated channel subfamily Q member 4",
"omim_id": [
"603537"
],
"orphanet": 122821,
"prev_name": [
"potassium voltage-gated channel, KQT-like subfamily, member 4",
"potassium channel, voltage gated KQT-like subfamily Q, member 4"
],
"prev_symbol": [
"DFNA2"
],
"pubmed_id": [
10025409,
16382104
],
"refseq_accession": [
"NM_004700"
],
"rgd_id": [
"RGD:61799"
],
"status": "Approved",
"symbol": "KCNQ4",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001cgh.2",
"uniprot_ids": [
"P56696"
],
"uuid": "790c26fc-046d-419a-85d7-b1f22f09b567",
"vega_id": "OTTHUMG00000007730"
},
"NCBI": {
"id": "9132"
}
},
"entId": "KCNQ4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6298",
"entType": "Gene",
"ldhId": "135641851",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641851",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "053_nuclear_KCNQ4",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "KCNQ4",
"preferredTranscript": "NM_004700.4"
}
],
"ns": "053",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243130",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243130",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--W"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243123",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243123",
"modified": "2022-08-18T19:13:44.249Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN054",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:44.669Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"054"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO6 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN054",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955116454000,
"agr": "HGNC:7605",
"alias_symbol": [
"KIAA0389"
],
"ccds_id": [
"CCDS34487",
"CCDS75481"
],
"date_approved_reserved": "1996-04-04",
"date_modified": "2021-05-26",
"date_name_changed": "2004-05-19",
"ena": [
"U90236",
"AB002387"
],
"ensembl_gene_id": "ENSG00000196586",
"entrez_id": "4646",
"gene_group": [
"Myosin heavy chains, class VI"
],
"gene_group_id": [
1101
],
"hgnc_id": "HGNC:7605",
"location": "6q14.1",
"location_sortable": "06q14.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=MYO6",
"LRG_438|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_438.xml"
],
"mane_select": [
"ENST00000369977.8",
"NM_004999.4"
],
"mgd_id": [
"MGI:104785"
],
"name": "myosin VI",
"omim_id": [
"600970"
],
"orphanet": 123648,
"prev_name": [
"deafness, autosomal recessive 37"
],
"prev_symbol": [
"DFNA22",
"DFNB37"
],
"pubmed_id": [
9259267,
11468689
],
"refseq_accession": [
"NM_004999"
],
"rgd_id": [
"RGD:1560646"
],
"status": "Approved",
"symbol": "MYO6",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003pih.2",
"uniprot_ids": [
"Q9UM54"
],
"uuid": "55f734b6-3be2-401d-bfcd-67db81dc9bc7",
"vega_id": "OTTHUMG00000015061"
},
"NCBI": {
"id": "4646"
}
},
"entId": "MYO6",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7605",
"entType": "Gene",
"ldhId": "135641855",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641855",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "054_nuclear_MYO6",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Dominant",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO6",
"preferredTranscript": "NM_004999.4"
}
],
"ns": "054",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243131",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243131",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--C"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243124",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243124",
"modified": "2022-08-18T19:13:48.137Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--B"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN055",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:48.554Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"055"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO7A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN055",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6750"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1452641873"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/78754"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
}
],
"comments": [
"This term's classification was reviewed in the context of the Strategic Refinement project (2023) and was determined to be excluded from the 'nervous system disorder' (MONDO:0005071) ontology branch (https://orcid.org/0000-0001-9310-0163) and from the 'metabolic disease' (MONDO:0005066) ontology branch (https://orcid.org/0000-0002-1780-5230)"
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush"
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
}
],
"xrefs": [
{
"val": "DOID:0050439"
},
{
"val": "GARD:7843"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:78754"
},
{
"val": "MESH:D052245"
},
{
"val": "MedDRA:10063396"
},
{
"val": "NANDO:1200941"
},
{
"val": "NCIT:C85217"
},
{
"val": "NORD:1816"
},
{
"val": "OMIMPS:276900"
},
{
"val": "Orphanet:886"
},
{
"val": "UMLS:C0271097"
},
{
"val": "icd11.foundation:1452641873"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642100",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642100",
"modified": "2025-10-07T15:46:46.842Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Yhee---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955117502500,
"agr": "HGNC:7606",
"alias_symbol": [
"NSRD2"
],
"ccds_id": [
"CCDS53684",
"CCDS53683"
],
"date_approved_reserved": "1992-06-08",
"date_modified": "2021-05-26",
"date_name_changed": "2005-09-12",
"ena": [
"U39226"
],
"ensembl_gene_id": "ENSG00000137474",
"entrez_id": "4647",
"gene_group": [
"A-kinase anchoring proteins",
"Myosin heavy chains, class VII",
"FERM domain containing"
],
"gene_group_id": [
396,
1102,
1293
],
"hgnc_id": "HGNC:7606",
"location": "11q13.5",
"location_sortable": "11q13.5",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org/",
"Mutations of the Myosin VIIa Gene|http://www.retina-international.org/files/sci-news/myomut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=MYO7A",
"LRG_1420|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1420.xml"
],
"mane_select": [
"ENST00000409709.9",
"NM_000260.4"
],
"mgd_id": [
"MGI:104510"
],
"name": "myosin VIIA",
"omim_id": [
"276903"
],
"orphanet": 123653,
"prev_name": [
"myosin VIIA (Usher syndrome 1B (autosomal recessive, severe))"
],
"prev_symbol": [
"USH1B",
"DFNB2",
"DFNA11"
],
"pubmed_id": [
8884266
],
"refseq_accession": [
"NM_000260"
],
"rgd_id": [
"RGD:628830"
],
"status": "Approved",
"symbol": "MYO7A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001oyc.3",
"uniprot_ids": [
"Q13402"
],
"uuid": "dba1b3d8-db0d-417e-a168-1285f826aa57",
"vega_id": "OTTHUMG00000152822"
},
"NCBI": {
"id": "4647"
}
},
"entId": "MYO7A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7606",
"entType": "Gene",
"ldhId": "135641853",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641853",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "055_nuclear_MYO7A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
},
{
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO7A",
"preferredTranscript": "NM_000260.4"
}
],
"ns": "055",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243132",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243132",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--P"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243125",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243125",
"modified": "2022-08-18T19:13:52.009Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--C"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN056",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:52.441Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"056"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC26A4 Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN056",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010134",
"lbl": "Pendred syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6878"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010134"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/pendred_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1156056623"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/82890"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C536648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/70348004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271829"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060744"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C121745"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_705"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/274600"
}
],
"definition": {
"val": "Pendred syndrome (PDS) is a clinically variable genetic disorder characterized by bilateral sensorineural hearing loss and euthyroid goiter.",
"xrefs": [
"Orphanet:705"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Pendred syndrome",
"xrefs": [
"DOID:0060744",
"MONDO:Lexical",
"NCIT:C121745",
"OMIM:274600",
"Orphanet:705",
"icd11.foundation:1156056623"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "TDH2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital hypothyroidism due to dyshormonogenesis 2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "deafness with goiter",
"xrefs": [
"DOID:0060744",
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "deafness with goitre"
},
{
"pred": "hasExactSynonym",
"val": "genetic defect in thyroid hormonogenesis 2B",
"xrefs": [
"DOID:0060744"
]
},
{
"pred": "hasExactSynonym",
"val": "goiter-deafness syndrome",
"xrefs": [
"DOID:0060744",
"OMIM:274600",
"Orphanet:705"
]
},
{
"pred": "hasExactSynonym",
"val": "hypothyroidism, congenital, due to dyshormonogenesis, 2B",
"xrefs": [
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"val": "thyroid dyshormonogenesis 2B",
"xrefs": [
"DOID:0060744",
"OMIM:274600"
]
},
{
"pred": "hasExactSynonym",
"val": "thyroid hormonogenesis, genetic defect in, 2B",
"xrefs": [
"OMIM:274600"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "PDS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "autosomal recessive sensorineural hearing impairment and goiter",
"xrefs": [
"GARD:0004271"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "autosomal recessive sensorineural hearing impairment and goitre"
}
],
"xrefs": [
{
"val": "DOID:0060744"
},
{
"val": "GARD:4271"
},
{
"val": "MEDGEN:82890"
},
{
"val": "MESH:C536648"
},
{
"val": "NCIT:C121745"
},
{
"val": "NORD:2030"
},
{
"val": "OMIM:274600"
},
{
"val": "Orphanet:705"
},
{
"val": "SCTID:70348004"
},
{
"val": "UMLS:C0271829"
},
{
"val": "icd11.foundation:1156056623"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010134",
"name": "Pendred syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal recessive inheritance",
"sepioID": "HP:0000007"
}
},
"entId": "MONDO:0010134",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010134",
"entType": "Disease",
"ldhId": "135642098",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642098",
"modified": "2025-10-07T15:44:07.088Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WFiS---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056963218800600,
"agr": "HGNC:8818",
"alias_name": [
"pendrin"
],
"alias_symbol": [
"PDS"
],
"bioparadigms_slc": "SLC26A4",
"ccds_id": [
"CCDS5746"
],
"date_approved_reserved": "1997-10-27",
"date_modified": "2016-10-05",
"date_name_changed": "2016-02-17",
"ena": [
"AF030880"
],
"ensembl_gene_id": "ENSG00000091137",
"entrez_id": "5172",
"gene_group": [
"Solute carriers"
],
"gene_group_id": [
752
],
"hgnc_id": "HGNC:8818",
"iuphar": "objectId:1100",
"location": "7q22.3",
"location_sortable": "07q22.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=SLC26A4"
],
"mane_select": [
"ENST00000644269.2",
"NM_000441.2"
],
"mgd_id": [
"MGI:1346029"
],
"name": "solute carrier family 26 member 4",
"omim_id": [
"605646"
],
"orphanet": 118821,
"prev_name": [
"solute carrier family 26, member 4",
"solute carrier family 26 (anion exchanger), member 4"
],
"prev_symbol": [
"DFNB4"
],
"pubmed_id": [
9500541,
11087667
],
"refseq_accession": [
"NM_000441"
],
"rgd_id": [
"RGD:3293"
],
"status": "Approved",
"symbol": "SLC26A4",
"ucsc_id": "uc003vep.4",
"uniprot_ids": [
"O43511"
],
"uuid": "597c9cdf-13fe-4340-9eb0-af0de850ad1c",
"vega_id": "OTTHUMG00000154807"
},
"NCBI": {
"id": "5172"
}
},
"entId": "SLC26A4",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8818",
"entType": "Gene",
"ldhId": "135641852",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641852",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "056_nuclear_SLC26A4",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0010134",
"preferredTitle": "Pendred syndrome"
}
],
"gene": "SLC26A4",
"preferredTranscript": "NM_000441.2"
}
],
"ns": "056",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243133",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243133",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--E"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
}
]
},
"ldhId": "643243126",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243126",
"modified": "2022-08-18T19:13:56.516Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN057",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:13:56.935Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"057"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TECTA Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN057",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056964847239200,
"agr": "HGNC:11720",
"ccds_id": [
"CCDS8434"
],
"date_approved_reserved": "1997-08-22",
"date_modified": "2016-10-05",
"ena": [
"AF055136"
],
"ensembl_gene_id": "ENSG00000109927",
"entrez_id": "7007",
"hgnc_id": "HGNC:11720",
"location": "11q23.3",
"location_sortable": "11q23.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org"
],
"mane_select": [
"ENST00000392793.6",
"NM_005422.4"
],
"mgd_id": [
"MGI:109575"
],
"name": "tectorin alpha",
"omim_id": [
"602574"
],
"orphanet": 120015,
"prev_symbol": [
"DFNA12",
"DFNA8",
"DFNB21"
],
"pubmed_id": [
9503015,
9590290
],
"refseq_accession": [
"NM_005422"
],
"rgd_id": [
"RGD:1309824"
],
"status": "Approved",
"symbol": "TECTA",
"ucsc_id": "uc058imn.1",
"uniprot_ids": [
"O75443"
],
"uuid": "04e5bd83-f9dc-46ff-b872-37188a91275d",
"vega_id": "OTTHUMG00000149908"
},
"NCBI": {
"id": "7007"
}
},
"entId": "TECTA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11720",
"entType": "Gene",
"ldhId": "135641850",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641850",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "057_nuclear_TECTA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "TECTA",
"preferredTranscript": "NM_005422.4"
}
],
"ns": "057",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243134",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243134",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--S"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
}
]
},
"ldhId": "643243127",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243127",
"modified": "2022-08-18T19:14:00.553Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--_"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN058",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:00.973Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"058"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for USH2A Version 2.0.0",
"version": "2.0.0"
},
"entId": "GN058",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019501",
"lbl": "Usher syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6750"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/usher_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10063396"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1452641873"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/78754"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D052245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0271097"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050439"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS276900"
}
],
"comments": [
"This term's classification was reviewed in the context of the Strategic Refinement project (2023) and was determined to be excluded from the 'nervous system disorder' (MONDO:0005071) ontology branch (https://orcid.org/0000-0001-9310-0163) and from the 'metabolic disease' (MONDO:0005066) ontology branch (https://orcid.org/0000-0002-1780-5230)"
],
"definition": {
"val": "A syndromic diseae characterized by the association of sensorineural deafness (usually congenital) with retinitis pigmentosa and progressive vision loss.",
"xrefs": [
"Orphanet:886"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "USH",
"xrefs": [
"Orphanet:886"
]
},
{
"pred": "hasExactSynonym",
"val": "Usher's syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasExactSynonym",
"val": "ush"
},
{
"pred": "hasNarrowSynonym",
"val": "deafness-retinitis pigmentosa syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasNarrowSynonym",
"val": "retinitis pigmentosa-deafness syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Graefe-Usher syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hallgren syndrome",
"xrefs": [
"GARD:0007843"
]
},
{
"pred": "hasRelatedSynonym",
"val": "dystrophia retinae pigmentosa-dysostosis syndrome",
"xrefs": [
"GARD:0007843"
]
}
],
"xrefs": [
{
"val": "DOID:0050439"
},
{
"val": "GARD:7843"
},
{
"val": "ICD10CM:H35.5"
},
{
"val": "MEDGEN:78754"
},
{
"val": "MESH:D052245"
},
{
"val": "MedDRA:10063396"
},
{
"val": "NANDO:1200941"
},
{
"val": "NCIT:C85217"
},
{
"val": "NORD:1816"
},
{
"val": "OMIMPS:276900"
},
{
"val": "Orphanet:886"
},
{
"val": "UMLS:C0271097"
},
{
"val": "icd11.foundation:1452641873"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019501",
"name": "Usher syndrome"
},
"entId": "MONDO:0019501",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019501",
"entType": "Disease",
"ldhId": "135642100",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642100",
"modified": "2025-10-07T15:46:46.842Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Yhee---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056966904545300,
"agr": "HGNC:12601",
"alias_symbol": [
"RP39"
],
"ccds_id": [
"CCDS31025",
"CCDS1516"
],
"date_approved_reserved": "1990-03-06",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-25",
"ena": [
"AF055580"
],
"ensembl_gene_id": "ENSG00000042781",
"entrez_id": "7399",
"gene_group": [
"Fibronectin type III domain containing",
"USH2 complex "
],
"gene_group_id": [
555,
1244
],
"hgnc_id": "HGNC:12601",
"location": "1q41",
"location_sortable": "01q41",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Mutations of the USH2a Gene|http://www.retina-international.org/files/sci-news/ush2amut.htm",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=USH2A"
],
"mane_select": [
"ENST00000307340.8",
"NM_206933.4"
],
"mgd_id": [
"MGI:1341292"
],
"name": "usherin",
"omim_id": [
"608400"
],
"orphanet": 120447,
"prev_name": [
"Usher syndrome 2A (autosomal recessive, mild)"
],
"prev_symbol": [
"USH2"
],
"pubmed_id": [
9624053,
10729113
],
"refseq_accession": [
"NM_007123"
],
"rgd_id": [
"RGD:628777"
],
"status": "Approved",
"symbol": "USH2A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001hku.1",
"uniprot_ids": [
"O75445"
],
"uuid": "b1118920-906c-4545-bc00-5b1a4cdb10a4",
"vega_id": "OTTHUMG00000037079"
},
"NCBI": {
"id": "7399"
}
},
"entId": "USH2A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12601",
"entType": "Gene",
"ldhId": "135641854",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641854",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyBC--D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "058_nuclear_USH2A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019501",
"preferredTitle": "Usher syndrome"
}
],
"gene": "USH2A",
"preferredTranscript": "NM_206933.4"
}
],
"ns": "058",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243135",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243135",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--G"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN005",
"releaseNotes": "\n(1) Removal of PM2 at moderate strength and use of the PM2 cutoff at supporting strength.\n(2) Functional assay strength and evidence using the criteria from Brnich et al., including downgrading PS3 to supporting for all specified COCH assays.\n(3) Removal of PP4 and PM1 specifications of genes that are outside of the HL VCEP defined scope",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"005"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2",
"version": "2.0.0"
},
"entId": "GN005",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637577",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637577",
"modified": "2023-09-29T15:16:45.390Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---A"
}
]
},
"ldhId": "643243128",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243128",
"modified": "2022-08-18T19:14:04.611Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--A"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN059",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:05.385Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"059"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGA2B Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN059",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100326",
"lbl": "Glanzmann thrombasthenia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100326"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1927726560"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/52736"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0040015"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_849"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS273800"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Glanzmann thrombasthenia",
"xrefs": [
"OMIMPS:273800",
"Orphanet:849",
"icd11.foundation:1927726560"
]
}
],
"xrefs": [
{
"val": "GARD:2478"
},
{
"val": "MEDGEN:52736"
},
{
"val": "NORD:1186"
},
{
"val": "OMIMPS:273800"
},
{
"val": "Orphanet:849"
},
{
"val": "UMLS:C0040015"
},
{
"val": "icd11.foundation:1927726560"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100326",
"name": "Glanzmann thrombasthenia"
},
"entId": "MONDO:0100326",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100326",
"entType": "Disease",
"ldhId": "467880243",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880243",
"modified": "2025-10-07T15:48:32.901Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aJUy---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056950415687700,
"agr": "HGNC:6138",
"alias_name": [
"protein phosphatase 1, regulatory subunit 93",
"platelet glycoprotein IIb of IIb/IIIa complex"
],
"alias_symbol": [
"CD41B",
"CD41",
"PPP1R93"
],
"ccds_id": [
"CCDS32665"
],
"cd": "CD41",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-04-13",
"date_name_changed": "2015-12-15",
"ensembl_gene_id": "ENSG00000005961",
"entrez_id": "3674",
"gene_group": [
"CD molecules",
"Protein phosphatase 1 regulatory subunits",
"Integrin alpha subunits"
],
"gene_group_id": [
471,
694,
1160
],
"hgnc_id": "HGNC:6138",
"iuphar": "objectId:2441",
"location": "17q21.31",
"location_sortable": "17q21.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_479|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_479.xml"
],
"mane_select": [
"ENST00000262407.6",
"NM_000419.5"
],
"mgd_id": [
"MGI:96601"
],
"name": "integrin subunit alpha 2b",
"omim_id": [
"607759"
],
"orphanet": 122690,
"prev_name": [
"integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B)",
"integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41)"
],
"prev_symbol": [
"GP2B"
],
"refseq_accession": [
"NM_000419"
],
"rgd_id": [
"RGD:1596428"
],
"status": "Approved",
"symbol": "ITGA2B",
"ucsc_id": "uc002igt.2",
"uniprot_ids": [
"P08514"
],
"uuid": "32a1045d-58d4-4bb1-8af8-bf83fcde871c",
"vega_id": "OTTHUMG00000177935"
},
"NCBI": {
"id": "3674"
}
},
"entId": "ITGA2B",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6138",
"entType": "Gene",
"ldhId": "135641918",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641918",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyA2--A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "059_nuclear_ITGA2B",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100326",
"preferredTitle": "Glanzmann thrombasthenia"
}
],
"gene": "ITGA2B",
"preferredTranscript": "NM_000419.4"
}
],
"ns": "059",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243136",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243136",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--h"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"description": "This version specified for the following genes: ITGA2B, ITGB3",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN011",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"011"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1",
"version": "2.1.0"
},
"entId": "GN011",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637583",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637583",
"modified": "2023-09-29T15:16:47.242Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--I"
}
]
},
"ldhId": "643243129",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243129",
"modified": "2022-08-18T19:14:09.167Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--D"
},
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN060",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:09.607Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"060"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGB3 Version 2.1.0",
"version": "2.1.0"
},
"entId": "GN060",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100326",
"lbl": "Glanzmann thrombasthenia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100326"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1927726560"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/52736"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0040015"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_849"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS273800"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Glanzmann thrombasthenia",
"xrefs": [
"OMIMPS:273800",
"Orphanet:849",
"icd11.foundation:1927726560"
]
}
],
"xrefs": [
{
"val": "GARD:2478"
},
{
"val": "MEDGEN:52736"
},
{
"val": "NORD:1186"
},
{
"val": "OMIMPS:273800"
},
{
"val": "Orphanet:849"
},
{
"val": "UMLS:C0040015"
},
{
"val": "icd11.foundation:1927726560"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100326",
"name": "Glanzmann thrombasthenia"
},
"entId": "MONDO:0100326",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100326",
"entType": "Disease",
"ldhId": "467880243",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880243",
"modified": "2025-10-07T15:48:32.901Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aJUy---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056950432465000,
"agr": "HGNC:6156",
"alias_name": [
"platelet glycoprotein IIIa",
"antigen CD61"
],
"alias_symbol": [
"CD61",
"GPIIIa"
],
"ccds_id": [
"CCDS11511"
],
"cd": "CD61",
"date_approved_reserved": "1988-06-09",
"date_modified": "2021-04-13",
"date_name_changed": "2015-12-15",
"ensembl_gene_id": "ENSG00000259207",
"entrez_id": "3690",
"gene_group": [
"CD molecules",
"Integrin beta subunits"
],
"gene_group_id": [
471,
1159
],
"hgnc_id": "HGNC:6156",
"iuphar": "objectId:2457",
"location": "17q21.32",
"location_sortable": "17q21.32",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_481|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_481.xml"
],
"mane_select": [
"ENST00000559488.7",
"NM_000212.3"
],
"mgd_id": [
"MGI:96612"
],
"name": "integrin subunit beta 3",
"omim_id": [
"173470"
],
"orphanet": 122704,
"prev_name": [
"integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61)"
],
"prev_symbol": [
"GP3A"
],
"pubmed_id": [
2454952
],
"refseq_accession": [
"NM_000212"
],
"rgd_id": [
"RGD:628868"
],
"status": "Approved",
"symbol": "ITGB3",
"ucsc_id": "uc002ilj.4",
"uniprot_ids": [
"P05106"
],
"uuid": "63283e01-3bbf-43c0-b2bf-dd051ab8f4a2",
"vega_id": "OTTHUMG00000171956"
},
"NCBI": {
"id": "3690"
}
},
"entId": "ITGB3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6156",
"entType": "Gene",
"ldhId": "135641919",
"ldhIri": "https://genboree.org/cspec/Gene/id/135641919",
"modified": "2021-10-14T11:36:27.781Z",
"modifier": "genbadmin",
"rev": "_h6SHyB---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "060_nuclear_ITGB3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0100326",
"preferredTitle": "Glanzmann thrombasthenia"
}
],
"gene": "ITGB3",
"preferredTranscript": "NM_000212.2"
}
],
"ns": "060",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243137",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243137",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--Y"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2021-11-01T00:00:00.000Z",
"description": "This version specified for the following genes: ITGA2B, ITGB3",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN011",
"notes": "",
"references": [],
"releaseNotes": "Updated MONDO ID for Glanzmann thrombasthenia from MONDO:0010119 to MONDO:0100326 (November 2021).",
"shortTitle": "ACMG variant classification Platelet Disorders",
"specificationSource": "https://clinicalgenome.org/docs/clingen-platelet-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2021-11-01T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"011"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1",
"version": "2.1.0"
},
"entId": "GN011",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637583",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637583",
"modified": "2023-09-29T15:16:47.242Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--I"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243130",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243130",
"modified": "2022-08-18T19:14:13.243Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykC--B"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN061",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:13.987Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"061"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for AKT3 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN061",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016054",
"lbl": "obsolete cerebral malformation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5114"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6876"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_cerebral_malformation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015219"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199633"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "brain malformation"
}
],
"xrefs": [
{
"val": "NANDO:2100217"
},
{
"val": "Orphanet:199633"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016054",
"name": "obsolete cerebral malformation"
},
"entId": "MONDO:0016054",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016054",
"entType": "Disease",
"ldhId": "467882125",
"ldhIri": "https://genboree.org/cspec/Disease/id/467882125",
"modified": "2025-10-07T15:45:45.208Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xlb2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056942263009300,
"agr": "HGNC:393",
"alias_name": [
"protein kinase B, gamma"
],
"alias_symbol": [
"PKBG",
"RAC-gamma",
"PRKBG"
],
"ccds_id": [
"CCDS31076",
"CCDS31077"
],
"date_approved_reserved": "1999-11-16",
"date_modified": "2021-05-26",
"date_name_changed": "2016-05-04",
"ena": [
"AF124141"
],
"ensembl_gene_id": "ENSG00000117020",
"entrez_id": "10000",
"enzyme_id": [
"2.7.11.1"
],
"gene_group": [
"Pleckstrin homology domain containing",
"AKT kinases"
],
"gene_group_id": [
682,
1900
],
"hgnc_id": "HGNC:393",
"iuphar": "objectId:2286",
"location": "1q43-q44",
"location_sortable": "01q43-q44",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1396|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1396.xml"
],
"mane_select": [
"ENST00000673466.1",
"NM_005465.7"
],
"mgd_id": [
"MGI:1345147"
],
"name": "AKT serine/threonine kinase 3",
"omim_id": [
"611223"
],
"orphanet": 299660,
"prev_name": [
"v-akt murine thymoma viral oncogene homolog 3"
],
"pubmed_id": [
10092583,
10208883
],
"refseq_accession": [
"NM_181690"
],
"rgd_id": [
"RGD:62390"
],
"status": "Approved",
"symbol": "AKT3",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc057qvr.1",
"uniprot_ids": [
"Q9Y243"
],
"uuid": "b261d7a3-a19d-49d9-9583-fa512693ef3b",
"vega_id": "OTTHUMG00000039994"
}
},
"entId": "AKT3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:393",
"entType": "Gene",
"ldhId": "467816839",
"ldhIri": "https://genboree.org/cspec/Gene/id/467816839",
"modified": "2021-10-14T11:36:28.929Z",
"modifier": "genbadmin",
"rev": "_h6SHyB2--E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "061_nuclear_AKT3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "AKT3",
"preferredTranscript": "NM_005465.4"
}
],
"ns": "061",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243138",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243138",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--i"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-10-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-05-14T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Brain Malformations",
"shortBaseName": "BrainMalform",
"shortTitle": "Brain Malformations VCEP",
"title": "Brain Malformations Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50020",
"entIri": "http://clinicalgenome.org/affiliation/50020",
"entType": "Organization",
"ldhId": "135637641",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637641",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243131",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243131",
"modified": "2022-11-11T18:08:11.946Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--B"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN062",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:18.044Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"062"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTOR Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN062",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016054",
"lbl": "obsolete cerebral malformation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5114"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6876"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_cerebral_malformation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015219"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199633"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "brain malformation"
}
],
"xrefs": [
{
"val": "NANDO:2100217"
},
{
"val": "Orphanet:199633"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016054",
"name": "obsolete cerebral malformation"
},
"entId": "MONDO:0016054",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016054",
"entType": "Disease",
"ldhId": "467882125",
"ldhIri": "https://genboree.org/cspec/Disease/id/467882125",
"modified": "2025-10-07T15:45:45.208Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xlb2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056954987479000,
"agr": "HGNC:3942",
"alias_name": [
"FK506 binding protein 12-rapamycin associated protein 2",
"rapamycin target protein",
"FKBP12-rapamycin complex-associated protein 1",
"FKBP-rapamycin associated protein",
"rapamycin associated protein FRAP2",
"dJ576K7.1 (FK506 binding protein 12-rapamycin associated protein 1)",
"rapamycin and FKBP12 target 1",
"mammalian target of rapamycin"
],
"alias_symbol": [
"RAFT1",
"RAPT1",
"FLJ44809"
],
"ccds_id": [
"CCDS127"
],
"cosmic": "MTOR",
"date_approved_reserved": "1995-07-18",
"date_modified": "2021-05-26",
"date_name_changed": "2017-08-04",
"date_symbol_changed": "2009-05-29",
"ena": [
"L34075"
],
"ensembl_gene_id": "ENSG00000198793",
"entrez_id": "2475",
"gene_group": [
"MTOR complex 1",
"MTOR complex 2",
"Armadillo like helical domain containing"
],
"gene_group_id": [
1332,
1333,
1492
],
"hgnc_id": "HGNC:3942",
"iuphar": "objectId:2109",
"location": "1p36.22",
"location_sortable": "01p36.22",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_734|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_734.xml"
],
"mane_select": [
"ENST00000361445.9",
"NM_004958.4"
],
"mgd_id": [
"MGI:1928394"
],
"name": "mechanistic target of rapamycin kinase",
"omim_id": [
"601231"
],
"orphanet": 431220,
"prev_name": [
"FK506 binding protein 12-rapamycin associated protein 1",
"mechanistic target of rapamycin (serine/threonine kinase)",
"mechanistic target of rapamycin"
],
"prev_symbol": [
"FRAP",
"FRAP2",
"FRAP1"
],
"pubmed_id": [
8008069,
8660990
],
"refseq_accession": [
"NM_004958"
],
"rgd_id": [
"RGD:68371"
],
"status": "Approved",
"symbol": "MTOR",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001asd.4",
"uniprot_ids": [
"P42345"
],
"uuid": "793d0551-866d-4b38-9f14-6483dee31064",
"vega_id": "OTTHUMG00000002001"
}
},
"entId": "MTOR",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3942",
"entType": "Gene",
"ldhId": "467840946",
"ldhIri": "https://genboree.org/cspec/Gene/id/467840946",
"modified": "2021-10-14T11:36:54.131Z",
"modifier": "genbadmin",
"rev": "_h6SHzpG--N"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "062_nuclear_MTOR",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "MTOR",
"preferredTranscript": "NM_004958.3"
}
],
"ns": "062",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243139",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243139",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--k"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-10-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-05-14T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Brain Malformations",
"shortBaseName": "BrainMalform",
"shortTitle": "Brain Malformations VCEP",
"title": "Brain Malformations Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50020",
"entIri": "http://clinicalgenome.org/affiliation/50020",
"entType": "Organization",
"ldhId": "135637641",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637641",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
}
]
},
"ldhId": "643243132",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243132",
"modified": "2022-11-11T18:08:12.113Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--E"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN063",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:21.885Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"063"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CA Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN063",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016054",
"lbl": "obsolete cerebral malformation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5114"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6876"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_cerebral_malformation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015219"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199633"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "brain malformation"
}
],
"xrefs": [
{
"val": "NANDO:2100217"
},
{
"val": "Orphanet:199633"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016054",
"name": "obsolete cerebral malformation"
},
"entId": "MONDO:0016054",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016054",
"entType": "Disease",
"ldhId": "467882125",
"ldhIri": "https://genboree.org/cspec/Disease/id/467882125",
"modified": "2025-10-07T15:45:45.208Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xlb2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056957518741500,
"agr": "HGNC:8975",
"alias_symbol": [
"PI3K"
],
"ccds_id": [
"CCDS43171"
],
"cosmic": "PIK3CA",
"date_approved_reserved": "1994-07-15",
"date_modified": "2021-05-26",
"date_name_changed": "2015-11-17",
"ensembl_gene_id": "ENSG00000121879",
"entrez_id": "5290",
"enzyme_id": [
"2.7.1.153"
],
"gene_group": [
"Phosphatidylinositol 3-kinase subunits"
],
"gene_group_id": [
831
],
"hgnc_id": "HGNC:8975",
"iuphar": "objectId:2153",
"location": "3q26.32",
"location_sortable": "03q26.32",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_310|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_310.xml"
],
"mane_select": [
"ENST00000263967.4",
"NM_006218.4"
],
"mgd_id": [
"MGI:1206581"
],
"name": "phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha",
"omim_id": [
"171834"
],
"orphanet": 117820,
"prev_name": [
"phosphoinositide-3-kinase, catalytic, alpha polypeptide",
"phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha"
],
"pubmed_id": [
1322797
],
"refseq_accession": [
"NM_006218"
],
"rgd_id": [
"RGD:620916"
],
"status": "Approved",
"symbol": "PIK3CA",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003fjk.4",
"uniprot_ids": [
"P42336"
],
"uuid": "d302e43e-131c-425a-8243-83dfa167561a",
"vega_id": "OTTHUMG00000157311"
}
},
"entId": "PIK3CA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8975",
"entType": "Gene",
"ldhId": "467845243",
"ldhIri": "https://genboree.org/cspec/Gene/id/467845243",
"modified": "2021-10-14T11:36:58.187Z",
"modifier": "genbadmin",
"rev": "_h6SHznu--F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "063_nuclear_PIK3CA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "PIK3CA",
"preferredTranscript": "NM_006218.3"
}
],
"ns": "063",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243140",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243140",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--I"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-10-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-05-14T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Brain Malformations",
"shortBaseName": "BrainMalform",
"shortTitle": "Brain Malformations VCEP",
"title": "Brain Malformations Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50020",
"entIri": "http://clinicalgenome.org/affiliation/50020",
"entType": "Organization",
"ldhId": "135637641",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637641",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243133",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243133",
"modified": "2022-11-11T18:08:12.252Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--C"
},
{
"entContent": {
"approvedOn": "2021-05-15T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN064",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:25.817Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"064"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R2 Version 1.0.0",
"version": "1.1.0"
},
"entId": "GN064",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016054",
"lbl": "obsolete cerebral malformation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000231",
"val": "http://purl.obolibrary.org/obo/OMO_0001000"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5114"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6752"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6876"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_syndromic_cerebral_malformation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015219"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_199633"
}
],
"deprecated": true,
"subsets": [
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "brain malformation"
}
],
"xrefs": [
{
"val": "NANDO:2100217"
},
{
"val": "Orphanet:199633"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016054",
"name": "obsolete cerebral malformation"
},
"entId": "MONDO:0016054",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016054",
"entType": "Disease",
"ldhId": "467882125",
"ldhIri": "https://genboree.org/cspec/Disease/id/467882125",
"modified": "2025-10-07T15:45:45.208Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xlb2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056957530275800,
"agr": "HGNC:8980",
"alias_name": [
"phosphoinositide-3-kinase regulatory subunit beta"
],
"alias_symbol": [
"P85B",
"p85"
],
"ccds_id": [
"CCDS12371"
],
"date_approved_reserved": "1992-12-08",
"date_modified": "2021-04-13",
"date_name_changed": "2015-11-17",
"ensembl_gene_id": "ENSG00000105647",
"entrez_id": "5296",
"gene_group": [
"SH2 domain containing"
],
"gene_group_id": [
741
],
"hgnc_id": "HGNC:8980",
"iuphar": "objectId:2504",
"location": "19p13.11",
"location_sortable": "19p13.11",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1392|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1392.xml"
],
"mane_select": [
"ENST00000222254.13",
"NM_005027.4"
],
"mgd_id": [
"MGI:1098772"
],
"name": "phosphoinositide-3-kinase regulatory subunit 2",
"omim_id": [
"603157"
],
"orphanet": 306122,
"prev_name": [
"phosphoinositide-3-kinase, regulatory subunit 2 (beta)"
],
"pubmed_id": [
1314371
],
"refseq_accession": [
"NM_005027"
],
"rgd_id": [
"RGD:68341"
],
"status": "Approved",
"symbol": "PIK3R2",
"ucsc_id": "uc002nia.3",
"uniprot_ids": [
"O00459"
],
"uuid": "6beadeec-7569-46fa-a896-b395675058fc",
"vega_id": "OTTHUMG00000183383"
}
},
"entId": "PIK3R2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8980",
"entType": "Gene",
"ldhId": "467845253",
"ldhIri": "https://genboree.org/cspec/Gene/id/467845253",
"modified": "2021-10-14T11:36:58.187Z",
"modifier": "genbadmin",
"rev": "_h6SHzmC--S"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "064_nuclear_PIK3R2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredMondoId": "MONDO:0016054",
"preferredTitle": "cerebral malformation"
}
],
"gene": "PIK3R2",
"preferredTranscript": "NM_005027.3"
}
],
"ns": "064",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243141",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243141",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--l"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-10-05T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-05-14T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Brain Malformations",
"shortBaseName": "BrainMalform",
"shortTitle": "Brain Malformations VCEP",
"title": "Brain Malformations Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50020",
"entIri": "http://clinicalgenome.org/affiliation/50020",
"entType": "Organization",
"ldhId": "135637641",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637641",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-08-19T00:00:00.000Z",
"description": "This version is specified for the following genes: AKT3, MTOR, PIK3CA, PIK3R2",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN018",
"releaseNotes": "The following criteria descriptions were modified for clarity based on feedback:\n\n* PS2 modified to make the distinction between PS2\\_strong vs PS2\\_moderate more clear and provide an example within the text\n* PS3 modified so it is clear the supplementary document applies to the SVI recommendation and not the animal model section\n* PS4’s upper margins were modified to make it clear that curators should not round off any of the values in Table 2A since it is not possible to obtain a value that is .99 or .49\n* BA1 and BS1 calculations corrected, rational provided in supplement\n* BS2 modified to make it clear that either homozygous instances in gnomAD or phenotyped family members can be utilized for this criterion\n* BP2 modified to indicate that this criterion can be used for either a cis or trans variant\n* BP4 modified to be consistent with detailed description provided later in the document",
"shortTitle": "Brain Malformations Specification",
"specificationSource": "https://clinicalgenome.org/docs/clingen-brain-malformations-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-1.1/",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-08-19T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"018"
],
"title": "ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0",
"version": "1.1.0"
},
"entId": "GN018",
"entType": "SequenceVariantInterpretation",
"ldhId": "467907148",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/467907148",
"modified": "2023-09-29T15:16:48.138Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyk---D"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243134",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243134",
"modified": "2022-11-11T18:08:12.421Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG--B"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN065",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:29.942Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"065"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYO15A Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN065",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955121696800,
"agr": "HGNC:7594",
"ccds_id": [
"CCDS42271"
],
"date_approved_reserved": "1998-05-29",
"date_modified": "2021-05-26",
"ena": [
"AF144094"
],
"ensembl_gene_id": "ENSG00000091536",
"entrez_id": "51168",
"gene_group": [
"Myosin heavy chains, class XV",
"FERM domain containing"
],
"gene_group_id": [
1105,
1293
],
"hgnc_id": "HGNC:7594",
"location": "17p11.2",
"location_sortable": "17p11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000647165.2",
"NM_016239.4"
],
"mgd_id": [
"MGI:1261811"
],
"name": "myosin XVA",
"omim_id": [
"602666"
],
"orphanet": 123641,
"prev_symbol": [
"DFNB3",
"MYO15"
],
"pubmed_id": [
9603736
],
"refseq_accession": [
"NM_016239"
],
"rgd_id": [
"RGD:1561873"
],
"status": "Approved",
"symbol": "MYO15A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc060cbc.1",
"uniprot_ids": [
"Q9UKN7"
],
"uuid": "36cbba76-4372-4b96-be9b-ca52c1a9053e",
"vega_id": "OTTHUMG00000059390"
}
},
"entId": "MYO15A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7594",
"entType": "Gene",
"ldhId": "467841177",
"ldhIri": "https://genboree.org/cspec/Gene/id/467841177",
"modified": "2021-10-14T11:36:54.363Z",
"modifier": "genbadmin",
"rev": "_h6SHzpK--K"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "065_nuclear_MYO15A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "MYO15A",
"preferredTranscript": "NM_016239.3"
}
],
"ns": "065",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243142",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243142",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--a"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN023",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"023"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1",
"version": "1.0.0"
},
"entId": "GN023",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243093",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243093",
"modified": "2023-09-29T15:16:48.775Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--A"
},
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243135",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243135",
"modified": "2022-08-18T19:14:33.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyju--A"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"hideFlag": true,
"legacyFullySuperseded": false,
"namespace": "GN066",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-18T19:14:33.937Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"066"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF Version 1.0.0",
"version": "1.0.0"
},
"entId": "GN066",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019497",
"lbl": "nonsyndromic genetic hearing loss",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/551"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019497"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6410/familial-deafness"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830101"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C580334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5680182"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0050563"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1154032108"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_87884"
}
],
"definition": {
"val": "A disease characterized by hearing loss that is not part of a larger syndrome.",
"xrefs": [
"MONDO:patterns/isolated"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic deafness",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasBroadSynonym",
"val": "nonsyndromic hearing loss",
"xrefs": [
"DOID:0050563",
"MONDO:patterns/isolated"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "nonsyndromic genetic hearing loss"
},
{
"pred": "hasExactSynonym",
"val": "nonsyndromic hereditary hearing loss",
"xrefs": [
"DOID:0050563"
]
},
{
"pred": "hasNarrowSynonym",
"val": "familial deafness",
"xrefs": [
"GARD:0006410"
]
},
{
"pred": "hasNarrowSynonym",
"val": "isolated genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "non-syndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
},
{
"pred": "hasNarrowSynonym",
"val": "nonsyndromic genetic deafness",
"xrefs": [
"Orphanet:87884"
]
}
],
"xrefs": [
{
"val": "DOID:0050563"
},
{
"val": "GARD:19091"
},
{
"val": "MEDGEN:1830101"
},
{
"val": "MESH:C580334"
},
{
"val": "Orphanet:87884"
},
{
"val": "UMLS:C5680182"
},
{
"val": "icd11.foundation:1154032108"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019497",
"name": "nonsyndromic genetic hearing loss",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0019497",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019497",
"entType": "Disease",
"ldhId": "135642095",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642095",
"modified": "2024-11-20T17:54:19.572Z",
"modifier": "cspecAdministrator",
"rev": "_iyoz73W---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056956881207300,
"agr": "HGNC:8515",
"alias_name": [
"fer-1-like family member 2"
],
"alias_symbol": [
"FER1L2",
"DFNB6"
],
"ccds_id": [
"CCDS46241",
"CCDS1725",
"CCDS74497",
"CCDS1726",
"CCDS1724"
],
"date_approved_reserved": "1999-03-31",
"date_modified": "2021-05-26",
"ena": [
"AF107403"
],
"ensembl_gene_id": "ENSG00000115155",
"entrez_id": "9381",
"gene_group": [
"Ferlin family"
],
"gene_group_id": [
828
],
"hgnc_id": "HGNC:8515",
"location": "2p23.3",
"location_sortable": "02p23.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Hereditary Hearing Loss Homepage|http://hereditaryhearingloss.org",
"CCHMC-BMI & UC Hearing Loss Mutation Database|https://research.cchmc.org/LOVD/home.php?select_db=OTOF"
],
"mane_select": [
"ENST00000272371.7",
"NM_194248.3"
],
"mgd_id": [
"MGI:1891247"
],
"name": "otoferlin",
"omim_id": [
"603681"
],
"orphanet": 124035,
"prev_symbol": [
"DFNB9"
],
"pubmed_id": [
10192385,
18381613
],
"refseq_accession": [
"NM_001287489"
],
"rgd_id": [
"RGD:620646"
],
"status": "Approved",
"symbol": "OTOF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002rhk.3",
"uniprot_ids": [
"Q9HC10"
],
"uuid": "e0ea26b4-7792-4b43-accc-e607201cc26d",
"vega_id": "OTTHUMG00000096977"
}
},
"entId": "OTOF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:8515",
"entType": "Gene",
"ldhId": "467844034",
"ldhIri": "https://genboree.org/cspec/Gene/id/467844034",
"modified": "2021-10-14T11:36:56.997Z",
"modifier": "genbadmin",
"rev": "_h6SHzmS--I"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "066_nuclear_OTOF",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal Recessive",
"preferredMondoId": "MONDO:0019497",
"preferredTitle": "nonsyndromic genetic deafness"
}
],
"gene": "OTOF",
"preferredTranscript": "NM_194248.2"
}
],
"ns": "066",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243143",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243143",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--K"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2017-11-14T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2018-08-15T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hearing Loss",
"shortBaseName": "HL",
"shortTitle": "Hearing Loss VCEP",
"title": "Hearing Loss Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50007",
"entIri": "http://clinicalgenome.org/affiliation/50007",
"entType": "Organization",
"ldhId": "135637631",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637631",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--P"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
},
{
"entContent": {
"approvedOn": "2022-03-30T00:00:00.000Z",
"description": "",
"hideFlag": false,
"legacy": true,
"legacyReplaced": false,
"namespace": "GN023",
"shortTitle": "Hearing Loss Variant Curation Expert Panel",
"specificationSource": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_otof_myo15a_v1.pdf",
"states": [
{
"current": true,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2022-03-30T00:00:00.000Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"023"
],
"title": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1",
"version": "1.0.0"
},
"entId": "GN023",
"entType": "SequenceVariantInterpretation",
"ldhId": "643243093",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243093",
"modified": "2023-09-29T15:16:48.775Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykK--A"
}
]
},
"ldhId": "643243136",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243136",
"modified": "2022-08-18T19:14:37.292Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--B"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:40:48.728Z",
"description": "SCN1A\n ",
"namespace": "GN067",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-25T12:32:02.290Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:56:03.778Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:34:25.209Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:24.019Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:04:23.222Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:42.792Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:22.670Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:40:48.728Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"067"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN067",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM6_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "*Clinical Criteria for Dravet Syndrome: Based on Li et al, 2021 (PMID: 34338318)
Major features
-Fever-sensitive seizures,
-Hemiclonic or tonic-clonic seizures,
-Status epilepticus
Minor criteria (at least 3)
-Normal development prior to seizure onset
-Seizure onset <=12m
-Developmental impairment by age 5y
-Intellectual disability",
"label": "PM6",
"ns": "067",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 1 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 0.5 points\n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nHemiplegic migraine: 0.25 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110674",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110674",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--X"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP2_nuclear_SCN1A",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "067",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110667",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110667",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--A"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "067",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members.\n\n\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members.\n\n5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members.\n\n3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110680",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110680",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--E"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP5_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "067",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110679",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110679",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--E"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP3_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP3",
"ns": "067",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool, with the following stipulations: with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110676",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110676",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--D"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP7_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "067",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110675",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110675",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--J"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "067",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110671",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110671",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--B"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP5_nuclear_SCN1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "067",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110669",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110669",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--G"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS3_nuclear_SCN1A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "067",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110664",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110664",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--D"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PS1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). As such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.",
"label": "PS1",
"ns": "067",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). \n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110684",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110684",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--N"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PS2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "*Clinical Criteria for Dravet Syndrome: Based on Li et al, 2021 (PMID: 34338318)
Major features
-Fever-sensitive seizures,
-Hemiclonic or tonic-clonic seizures,
-Status epilepticus
Minor criteria (at least 3)
-Normal development prior to seizure onset
-Seizure onset <=12m
-Developmental impairment by age 5y
-Intellectual disability
",
"label": "PS2",
"ns": "067",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110683",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110683",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--M"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "067",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0004% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110678",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110678",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--D"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "067",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110668",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110668",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--B"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BS4_nuclear_SCN1A",
"additionalComments": "Reduced penetrance, variable expressivity and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "067",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110665",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110665",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--A"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM5_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channels genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). In other words, the sodium channel genes share 87.7% (SCN2A), 84.7% (SCN3A), and 77.0% (SCN8A) amino acid sequence similarly with SCN1A (Ensembl). \n\nThe four functional homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "067",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Novel missense change at an amino acid residue in the same gene where a different missense variant was determined to be Pathogenic.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic** or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110663",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110663",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--H"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PS4_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "*Clinical Criteria for Dravet Syndrome: Based on Li et al, 2021 (PMID: 34338318)
Major features
-Fever-sensitive seizures,
-Hemiclonic or tonic-clonic seizures,
-Status epilepticus
Minor criteria (at least 3)
-Normal development prior to seizure onset
-Seizure onset <=12m
-Developmental impairment by age 5y
-Intellectual disability",
"label": "PS4",
"ns": "067",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDravet\\*: 2 points\n\nGenetic Epilepsy with Febrile Seizures Plus: 1 point\n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nHemiplegic migraine: 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110661",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110661",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--B"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM4_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "067",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110659",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110659",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--G"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP6_nuclear_SCN1A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "067",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110685",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110685",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq---"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PP4_nuclear_SCN1A",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "067",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110682",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110682",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--H"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PS3_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "067",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110677",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110677",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--K"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BA1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "067",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above 0.02% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110673",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110673",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--C"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM3_nuclear_SCN1A",
"additionalComments": "SCN1A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "067",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110670",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110670",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--C"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "067",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110662",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110662",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--W"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP4_nuclear_SCN1A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "067",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110686",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110686",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--I"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP3_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "067",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110681",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110681",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--L"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PVS1_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"instructionsToUse": " For a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "067",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110672",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110672",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--I"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_BP1_nuclear_SCN1A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "067",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110666",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110666",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--E"
},
{
"created": "2024-03-19T18:40:49.390Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "067_PM2_nuclear_SCN1A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN1A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "067",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746110660",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746110660",
"modified": "2024-03-19T18:40:49.390Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018214",
"lbl": "generalized epilepsy with febrile seizures plus",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5957"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7924"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8280"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0018214"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/generalized_epilepsy_with_febrile_seizures_plus"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://www.epilepsydiagnosis.org/syndrome/fbp-overview.html"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/503203"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C565808"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/699688008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3502809"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060170"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C122811"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_36387"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS604233"
}
],
"definition": {
"val": "A familial epilepsy syndrome in which family members display a seizure disorder from the generalized epilepsy with febrile seizures plus spectrum which ranges from simple febrile seizures (FS) to the more severe phenotype of myoclonic-astatic epilepsy (MAE) or Dravet syndrome (DS).",
"xrefs": [
"Orphanet:36387"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "GEFS+",
"xrefs": [
"DOID:0060170",
"NCIT:C122811",
"Orphanet:36387"
]
},
{
"pred": "hasExactSynonym",
"val": "epilepsy, generalized, with febrile seizures plus",
"xrefs": [
"OMIMPS:604233"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "generalised epilepsy with febrile seizures-plus"
},
{
"pred": "hasExactSynonym",
"val": "generalized epilepsy with febrile seizures plus",
"xrefs": [
"DOID:0060170",
"NCIT:C122811",
"https://www.clinicalgenome.org/affiliation/40005/"
]
},
{
"pred": "hasExactSynonym",
"val": "genetic epilepsy with febrile seizures plus",
"xrefs": [
"https://www.clinicalgenome.org/affiliation/40005/",
"https://www.epilepsydiagnosis.org/syndrome/fbp-overview.html"
]
},
{
"pred": "hasExactSynonym",
"val": "genetic epilepsy with febrile seizures-plus",
"xrefs": [
"Orphanet:36387",
"https://www.clinicalgenome.org/affiliation/40005/"
]
}
],
"xrefs": [
{
"val": "DOID:0060170"
},
{
"val": "GARD:18641"
},
{
"val": "MEDGEN:503203"
},
{
"val": "MESH:C565808"
},
{
"val": "NCIT:C122811"
},
{
"val": "OMIMPS:604233"
},
{
"val": "Orphanet:36387"
},
{
"val": "SCTID:699688008"
},
{
"val": "UMLS:C3502809"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018214",
"name": "generalized epilepsy with febrile seizures plus"
},
"entId": "MONDO:0018214",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018214",
"entType": "Disease",
"ldhId": "467877022",
"ldhIri": "https://genboree.org/cspec/Disease/id/467877022",
"modified": "2025-10-07T15:46:23.439Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YKnu---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100062",
"lbl": "genetic developmental and epileptic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/19"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8274"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100062"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/developmental_and_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/early_infantile_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015921"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0024321"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100022"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-10-10T22:04:15Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0112202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C122814"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS308350"
}
],
"comments": [
"Individuals, both male and female, have been reported with variants in the GABRB3 gene. De novo and familial cases have been reported, with mostly missense and a few nonsense variants identified as causative. These patients have been described in the literature as having a range of phenotypes characterized as epileptic encephalopathy, Lennox-Gastaut syndrome, Dravet syndrome-like, and childhood absence epilepsy. Severity of intellectual disability is variable among reported probands, as is the age of onset of seizure phenotypes. In one case of epileptic encephalopathy, for example, the individual presented with severe intellectual disability while seizures onset at 12 years old. Additionally, individuals have been reported with the same de novo missense variants, and have been described with varying phenotypes. (PMID:26544041, PMID:26704558, PMID:26645412, PMID:26993267, PMID:27476654)"
],
"definition": {
"val": "A complex neurodevelopmental disorder characterized by a range of developmental delays and epileptic encephalopathy phenotypes. Seizure onset is variable and intellectual disability is variable in presence and severity.",
"xrefs": [
"PMID:28276062"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "developmental and epileptic encephalopathy",
"xrefs": [
"DOID:0112202",
"NCIT:C122814",
"OMIMPS:308350",
"https://orcid.org/0000-0001-8486-0558"
]
},
{
"pred": "hasNarrowSynonym",
"val": "hereditary developmental and epileptic encephalopathy",
"xrefs": [
"https://orcid.org/0000-0001-5208-3432"
]
}
],
"xrefs": [
{
"val": "DOID:0112202"
},
{
"val": "GARD:9255"
},
{
"val": "ICD9:345.10"
},
{
"val": "NANDO:1200593"
},
{
"val": "NCIT:C122814"
},
{
"val": "OMIMPS:308350"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100062",
"name": "genetic developmental and epileptic encephalopathy"
},
"entId": "MONDO:0100062",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100062",
"entType": "Disease",
"ldhId": "467881472",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881472",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFoe--D"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100135",
"lbl": "Dravet syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100135"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10430/dravet-syndrome"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://www.epilepsydiagnosis.org/syndrome/dravet-overview.html"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1255654700"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/148243"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/230437002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0751122"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/G40.83"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080422"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C116573"
}
],
"comments": [
"This is a distinct class from MONDO:0100079 epileptic encephalopathy, early infantile 6. See https://github.com/monarch-initiative/mondo/issues/745"
],
"definition": {
"val": "Dravet syndrome is a channelopathy with epilepsy of with onset during the first year of life, typically 4-5 months, characterized by status epilepticus and a variety of drug-resistant seizures often induced by fever, presenting in previously healthy children, and which frequently leads to cognitive and motor impairment. Dravet differs from other channelopathies usually due to a mutation in SCN1A.",
"xrefs": [
"https://orcid.org/0000-0001-5208-3432",
"https://orcid.org/0000-0001-7090-9648",
"https://orcid.org/0000-0002-6601-2165"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "DS"
},
{
"pred": "hasExactSynonym",
"val": "Dravet",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"val": "Dravet syndrome",
"xrefs": [
"DOID:0080422",
"NCIT:C116573",
"icd11.foundation:1255654700"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "SME",
"xrefs": [
"GARD:0010430"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "SMEB",
"xrefs": [
"PMID:37498137"
]
},
{
"pred": "hasExactSynonym",
"val": "myoclonic epilepsy, severe, of infancy",
"xrefs": [
"GARD:0010430"
]
},
{
"pred": "hasExactSynonym",
"val": "severe myoclonic epilepsy of infancy",
"xrefs": [
"DOID:0080422",
"NCIT:C116573",
"PMID:37498137"
]
}
],
"xrefs": [
{
"val": "DOID:0060171"
},
{
"val": "DOID:0080422"
},
{
"val": "GARD:10430"
},
{
"val": "ICD10CM:G40.83"
},
{
"val": "ICD9:345.10"
},
{
"val": "MEDGEN:148243"
},
{
"val": "NANDO:1200587"
},
{
"val": "NANDO:2200877"
},
{
"val": "NCIT:C116573"
},
{
"val": "NORD:1061"
},
{
"val": "SCTID:230437002"
},
{
"val": "UMLS:C0751122"
},
{
"val": "icd11.foundation:1255654700"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100135",
"name": "Dravet syndrome"
},
"entId": "MONDO:0100135",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100135",
"entType": "Disease",
"ldhId": "467880999",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880999",
"modified": "2025-10-07T15:48:31.234Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aHXu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962494234600,
"agr": "HGNC:10585",
"alias_symbol": [
"Nav1.1",
"GEFSP2",
"HBSCI",
"NAC1",
"SMEI"
],
"ccds_id": [
"CCDS54413",
"CCDS86891",
"CCDS54414",
"CCDS33316"
],
"date_approved_reserved": "1988-11-28",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
"ena": [
"AB093548"
],
"ensembl_gene_id": "ENSG00000144285",
"entrez_id": "6323",
"gene_group": [
"Sodium voltage-gated channel alpha subunits"
],
"gene_group_id": [
1203
],
"hgnc_id": "HGNC:10585",
"iuphar": "objectId:578",
"location": "2q24.3",
"location_sortable": "02q24.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/SCN1A",
"LRG_8|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_8.xml"
],
"mane_select": [
"ENST00000674923.1",
"NM_001165963.4"
],
"mgd_id": [
"MGI:98246"
],
"name": "sodium voltage-gated channel alpha subunit 1",
"omim_id": [
"182389"
],
"orphanet": 118489,
"prev_name": [
"febrile convulsions 3",
"sodium channel, voltage-gated, type I, alpha subunit",
"sodium channel, voltage gated, type I alpha subunit"
],
"prev_symbol": [
"SCN1",
"FEB3"
],
"pubmed_id": [
8062593,
16382098,
11823106
],
"refseq_accession": [
"NM_006920"
],
"rgd_id": [
"RGD:69364"
],
"status": "Approved",
"symbol": "SCN1A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc061peu.1",
"uniprot_ids": [
"P35498"
],
"uuid": "688ebd60-2b4e-44dd-8f2e-0bf6841ca56d",
"vega_id": "OTTHUMG00000044173"
}
},
"entId": "SCN1A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10585",
"entType": "Gene",
"ldhId": "467855388",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855388",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
"rev": "_h6SHz8u--_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "067_nuclear_SCN1A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100135",
"preferredTitle": "Dravet syndrome"
},
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0018214",
"preferredTitle": "generalized epilepsy with febrile seizures plus"
},
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100062",
"preferredTitle": "developmental and epileptic encephalopathy"
}
],
"gene": "SCN1A",
"preferredTranscript": "NM_001165963.3"
}
],
"ns": "067",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243144",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243144",
"modified": "2024-03-19T18:40:49.316Z",
"modifier": "laceysmith",
"rev": "_h6SHyTa--E"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Epilepsy SCN",
"approval": {
"step1": {
"approvalDate": "2021-09-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-04-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-18T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-03-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Epilepsy Sodium Channel",
"shortBaseName": "Epilepsy SCN",
"shortTitle": "Epilepsy Sodium Channel VCEP",
"title": "Epilepsy Sodium Channel Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50105",
"entIri": "http://clinicalgenome.org/affiliation/50105",
"entType": "Organization",
"ldhId": "639508904",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508904",
"modified": "2024-03-05T21:54:58.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--k"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243137",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243137",
"modified": "2024-03-19T18:40:49.258Z",
"modifier": "laceysmith",
"rev": "_h6SHykG--K"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:41:33.170Z",
"description": "SCN2A",
"namespace": "GN068",
"releaseNotes": "",
"releasedUnderRevision": true,
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-25T17:16:49.110Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:57:33.256Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:34:48.630Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:28.452Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:04:45.784Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:44.233Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:24.630Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:41:33.170Z"
},
"name": "Released"
},
{
"current": true,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2025-09-04T17:42:03.882Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"068"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN068",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS2",
"ns": "068",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111567",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111567",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--M"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "068",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111562",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111562",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--L"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "068",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111560",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111560",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--K"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP7_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "068",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111559",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111559",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--b"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BA1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency is above 0.02% in GnomAD or other large population database. ",
"label": "BA1",
"ns": "068",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111557",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111557",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--a"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM3_nuclear_SCN2A",
"additionalComments": "SCN2A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "068",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111554",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111554",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--J"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS3_nuclear_SCN2A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic ID/ASD, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "068",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111548",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111548",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--G"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS4_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS4",
"ns": "068",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 - 15.5 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 - 3.5 points** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 - 1.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111545",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111545",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--Y"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "068",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111544",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111544",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--G"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelopmental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). As such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.\n\nPS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859.",
"label": "PS1",
"ns": "068",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). \n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111568",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111568",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--N"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PS3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "068",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111561",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111561",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--c"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP1_nuclear_SCN2A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "068",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111550",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111550",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--H"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP4_nuclear_SCN2A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "068",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)) using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111570",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111570",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--C"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "068",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111564",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111564",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--d"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP5_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "068",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111563",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111563",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--K"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM6_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described by Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PM6",
"ns": "068",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111558",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111558",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--B"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "068",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111555",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111555",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--_"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS4_nuclear_SCN2A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "068",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111549",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111549",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--I"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP4_nuclear_SCN2A",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "068",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111566",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111566",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--L"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP3_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "068",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111565",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111565",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--M"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PVS1_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1591\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "068",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591.\n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111556",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111556",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--A"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BS2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "068",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual with full penetrance expected at an early age.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111552",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111552",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--J"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM5_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "068",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111547",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111547",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO--F"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP6_nuclear_SCN2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "068",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111569",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111569",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK---"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP5_nuclear_SCN2A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "068",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111553",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111553",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--_"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PP2_nuclear_SCN2A",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "068",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111551",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111551",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--Z"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_BP2_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "068",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111546",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111546",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--H"
},
{
"created": "2024-03-19T18:41:33.659Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "068_PM4_nuclear_SCN2A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN2A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "068",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746111543",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746111543",
"modified": "2024-03-19T18:41:33.659Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--F"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962496331800,
"agr": "HGNC:10588",
"alias_symbol": [
"Nav1.2",
"HBSCII",
"HBSCI"
],
"ccds_id": [
"CCDS33314",
"CCDS33313"
],
"date_approved_reserved": "1992-08-07",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
"date_symbol_changed": "2007-01-23",
"ena": [
"AB208888"
],
"ensembl_gene_id": "ENSG00000136531",
"entrez_id": "6326",
"gene_group": [
"Sodium voltage-gated channel alpha subunits"
],
"gene_group_id": [
1203
],
"hgnc_id": "HGNC:10588",
"iuphar": "objectId:579",
"location": "2q24.3",
"location_sortable": "02q24.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000375437.7",
"NM_001040142.2"
],
"mgd_id": [
"MGI:98248"
],
"name": "sodium voltage-gated channel alpha subunit 2",
"omim_id": [
"182390"
],
"orphanet": 118500,
"prev_name": [
"sodium channel, voltage-gated, type II, alpha 2 polypeptide",
"sodium channel, voltage-gated, type II, alpha 1 polypeptide",
"sodium channel, voltage-gated, type II, alpha subunit",
"sodium channel, voltage gated, type II alpha subunit"
],
"prev_symbol": [
"SCN2A1",
"SCN2A2"
],
"pubmed_id": [
1317301,
16382098
],
"refseq_accession": [
"NM_021007"
],
"rgd_id": [
"RGD:3632"
],
"status": "Approved",
"symbol": "SCN2A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc061pdo.1",
"uniprot_ids": [
"Q99250"
],
"uuid": "e0f45eba-81a1-4a2f-9f03-8505fd16a9a2",
"vega_id": "OTTHUMG00000044172"
}
},
"entId": "SCN2A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10588",
"entType": "Gene",
"ldhId": "467855391",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855391",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
"rev": "_h6SHz8C--P"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "068_nuclear_SCN2A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "SCN2A",
"preferredTranscript": "NM_021007.2"
}
],
"ns": "068",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243145",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243145",
"modified": "2024-03-19T18:41:33.589Z",
"modifier": "laceysmith",
"rev": "_h6SHyTa--J"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Epilepsy SCN",
"approval": {
"step1": {
"approvalDate": "2021-09-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-04-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-18T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-03-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Epilepsy Sodium Channel",
"shortBaseName": "Epilepsy SCN",
"shortTitle": "Epilepsy Sodium Channel VCEP",
"title": "Epilepsy Sodium Channel Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50105",
"entIri": "http://clinicalgenome.org/affiliation/50105",
"entType": "Organization",
"ldhId": "639508904",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508904",
"modified": "2024-03-05T21:54:58.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--k"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243138",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243138",
"modified": "2025-09-04T17:42:04.295Z",
"modifier": "cspecAdministrator",
"rev": "_kPVQNv2---"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:42:37.373Z",
"description": "SCN3A",
"namespace": "GN069",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T15:36:15.462Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:58:27.926Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:11.910Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:31.278Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:05:04.244Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:46.152Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:26.429Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:42:37.373Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"069"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN069",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP4_nuclear_SCN3A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "069",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112478",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112478",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--k"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.",
"label": "PS1",
"ns": "069",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112476",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112476",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--R"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP5_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "069",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112471",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112471",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--F"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS3_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "069",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112469",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112469",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--i"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP7_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "069",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112467",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112467",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--h"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BA1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency is above 0.02% in GnomAD or other large population database. ",
"label": "BA1",
"ns": "069",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112465",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112465",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--g"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BS4_nuclear_SCN3A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "069",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112457",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112457",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--f"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BS2_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "069",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112460",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112460",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--D"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP2_nuclear_SCN3A",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "069",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112459",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112459",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--A"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BS3_nuclear_SCN3A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "069",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112456",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112456",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--e"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS4_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "069",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112453",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112453",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--B"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PS2_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "069",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 1 point\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112475",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112475",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--H"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "069",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112472",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112472",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--D"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BS1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "069",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112470",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112470",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--j"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM6_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "069",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nDevelopmental and Epileptic Encephalopathy: 0.5 points\n\nOther phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112466",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112466",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--E"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PVS1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo NMD: p.Thr1586 \n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "069",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. \n\nIn-frame exons: 1, 7, 8, 12, 17, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112464",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112464",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--D"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM5_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "069",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112455",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112455",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--P"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP2_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "069",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112454",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112454",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--C"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP3_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "069",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112473",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112473",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--Q"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP3_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "069",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112468",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112468",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--C"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM3_nuclear_SCN3A",
"additionalComments": "SCN3A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "069",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112462",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112462",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--E"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP5_nuclear_SCN3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "069",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112461",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112461",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--B"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM2_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "069",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112452",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112452",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--A"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM4_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "069",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112451",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112451",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--O"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP6_nuclear_SCN3A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "069",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112477",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112477",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--I"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PP4_nuclear_SCN3A",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "069",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112474",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112474",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--G"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_PM1_nuclear_SCN3A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "069",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112463",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112463",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqS--G"
},
{
"created": "2024-03-19T18:42:37.986Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "069_BP1_nuclear_SCN3A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN3A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "069",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746112458",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746112458",
"modified": "2024-03-19T18:42:37.986Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100062",
"lbl": "genetic developmental and epileptic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/19"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8274"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100062"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/developmental_and_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/early_infantile_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015921"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0024321"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100022"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-10-10T22:04:15Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0112202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C122814"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS308350"
}
],
"comments": [
"Individuals, both male and female, have been reported with variants in the GABRB3 gene. De novo and familial cases have been reported, with mostly missense and a few nonsense variants identified as causative. These patients have been described in the literature as having a range of phenotypes characterized as epileptic encephalopathy, Lennox-Gastaut syndrome, Dravet syndrome-like, and childhood absence epilepsy. Severity of intellectual disability is variable among reported probands, as is the age of onset of seizure phenotypes. In one case of epileptic encephalopathy, for example, the individual presented with severe intellectual disability while seizures onset at 12 years old. Additionally, individuals have been reported with the same de novo missense variants, and have been described with varying phenotypes. (PMID:26544041, PMID:26704558, PMID:26645412, PMID:26993267, PMID:27476654)"
],
"definition": {
"val": "A complex neurodevelopmental disorder characterized by a range of developmental delays and epileptic encephalopathy phenotypes. Seizure onset is variable and intellectual disability is variable in presence and severity.",
"xrefs": [
"PMID:28276062"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "developmental and epileptic encephalopathy",
"xrefs": [
"DOID:0112202",
"NCIT:C122814",
"OMIMPS:308350",
"https://orcid.org/0000-0001-8486-0558"
]
},
{
"pred": "hasNarrowSynonym",
"val": "hereditary developmental and epileptic encephalopathy",
"xrefs": [
"https://orcid.org/0000-0001-5208-3432"
]
}
],
"xrefs": [
{
"val": "DOID:0112202"
},
{
"val": "GARD:9255"
},
{
"val": "ICD9:345.10"
},
{
"val": "NANDO:1200593"
},
{
"val": "NCIT:C122814"
},
{
"val": "OMIMPS:308350"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100062",
"name": "genetic developmental and epileptic encephalopathy"
},
"entId": "MONDO:0100062",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100062",
"entType": "Disease",
"ldhId": "467881472",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881472",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFoe--D"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962497380400,
"agr": "HGNC:10590",
"alias_symbol": [
"Nav1.3"
],
"ccds_id": [
"CCDS33312",
"CCDS46440"
],
"date_approved_reserved": "1992-04-10",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
"ena": [
"AF035685"
],
"ensembl_gene_id": "ENSG00000153253",
"entrez_id": "6328",
"gene_group": [
"Sodium voltage-gated channel alpha subunits"
],
"gene_group_id": [
1203
],
"hgnc_id": "HGNC:10590",
"iuphar": "objectId:580",
"location": "2q24.3",
"location_sortable": "02q24.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000283254.12",
"NM_006922.4"
],
"mgd_id": [
"MGI:98249"
],
"name": "sodium voltage-gated channel alpha subunit 3",
"omim_id": [
"182391"
],
"orphanet": 471032,
"prev_name": [
"sodium channel, voltage-gated, type III, alpha polypeptide",
"sodium channel, voltage-gated, type III, alpha subunit",
"sodium channel, voltage gated, type III alpha subunit"
],
"pubmed_id": [
9589372,
16382098
],
"refseq_accession": [
"NM_006922"
],
"rgd_id": [
"RGD:3635"
],
"status": "Approved",
"symbol": "SCN3A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002ucx.4",
"uniprot_ids": [
"Q9NY46"
],
"uuid": "20128529-f868-488c-b846-1b5041b786f1",
"vega_id": "OTTHUMG00000044171"
}
},
"entId": "SCN3A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10590",
"entType": "Gene",
"ldhId": "467855393",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855393",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
"rev": "_h6SHz8q--w"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "069_nuclear_SCN3A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100062",
"preferredTitle": "developmental and epileptic encephalopathy"
}
],
"gene": "SCN3A",
"preferredTranscript": "NM_006922.3"
}
],
"ns": "069",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243146",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243146",
"modified": "2024-03-19T18:42:37.908Z",
"modifier": "laceysmith",
"rev": "_h6SHyTW--O"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Epilepsy SCN",
"approval": {
"step1": {
"approvalDate": "2021-09-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-04-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-18T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-03-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Epilepsy Sodium Channel",
"shortBaseName": "Epilepsy SCN",
"shortTitle": "Epilepsy Sodium Channel VCEP",
"title": "Epilepsy Sodium Channel Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50105",
"entIri": "http://clinicalgenome.org/affiliation/50105",
"entType": "Organization",
"ldhId": "639508904",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508904",
"modified": "2024-03-05T21:54:58.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--k"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243139",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243139",
"modified": "2024-03-19T18:42:37.860Z",
"modifier": "laceysmith",
"rev": "_h6SHykW--P"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:43:29.634Z",
"description": "SCN8A",
"namespace": "GN070",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T16:02:50.886Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T19:59:43.168Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:32.036Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:32:41.896Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:05:22.669Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:47.538Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:28.189Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:43:29.634Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"070"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN070",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP3_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "070",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113410",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113410",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa--C"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS3_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "If a variant is found to have differences from wildtype of multiple levels of strength (example: strong level of evidence in peak current and moderate level of evidence in persistent current), use the highest level of evidence (capping at strong). If a variant has been studied in multiple publications, use the strongest level of evidence available.",
"label": "PS3",
"ns": "070",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 72.7% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 135% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.2 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 4.1 mV (absolute value).\n* Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* In patch clamping experiments: Peak current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is less than or equal to 80.6% of wildtype.\n* In patch clamping experiments: Persistent current as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is greater than or equal to 125% of wildtype.\n* In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 2.1 mV (absolute value).\n* In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology ([https://bioportal.bioontology.org/ontologies/FENICS](https://bioportal.bioontology.org/ontologies/FENICS)) is shifted by at least 3.0 mV (absolute value).\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113406",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113406",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP3_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "070",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113405",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113405",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--p"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP5_nuclear_SCN8A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "070",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113398",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113398",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqW--A"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP2_nuclear_SCN8A",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "070",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113396",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113396",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--m"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM5_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remains largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PM5.\n\n**Rule Combining Stipulation**: If PM5\\_Strong is reached, and the variant falls within a PM1 region, then do not add PM1 with PM5\\_Strong.",
"label": "PM5",
"ns": "070",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. \n* \\>1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be **Pathogenic**or **Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113392",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113392",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqW---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS4_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS4",
"ns": "070",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 - 15.5 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 - 3.5 points** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 - 1.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113390",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113390",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--I"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM2_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "070",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113389",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113389",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--H"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP5_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "070",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113408",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113408",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa--A"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "070",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113407",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113407",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa--_"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP2_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "070",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113391",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113391",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpq--J"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP4_nuclear_SCN8A",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "070",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113415",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113415",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--q"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "070",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>=7 independent meioses",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5-6 independent meioses",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3-4 independent meioses",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113409",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113409",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa--B"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BA1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency is above 0.02% in GnomAD or other large population database. ",
"label": "BA1",
"ns": "070",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.01%** is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113402",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113402",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS--B"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM3_nuclear_SCN8A",
"additionalComments": "SCN8A is associated with autosomal dominant inheritance. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "070",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113399",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113399",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS--_"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS3_nuclear_SCN8A",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "070",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113393",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113393",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--l"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP6_nuclear_SCN8A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "070",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113414",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113414",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--G"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS2_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PS2",
"ns": "070",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 1 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113412",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113412",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS--C"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PP4_nuclear_SCN8A",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "070",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113411",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113411",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqa--D"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM6_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Complex Neurodevelopmental Disorder (MONDO:0100038), as further described in Helbig et al, 2018 (PMID: 30311377), represents the broad and overlapping clinical spectrum that can include epilepsy, developmental delay, intellectual disability and autism spectrum disorder.",
"label": "PM6",
"ns": "070",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\n* Complex Neurodevelopmental Disorder: 0.5 points\n* Other phenotypes not consistent w/neurodevelopmental disorder: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113403",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113403",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--o"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Pathogenic Enriched Regions (PERs): Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants. Pérez-Palma, 2020 [PMID: 31871067](https://pubmed.ncbi.nlm.nih.gov/31871067/) & Lal et al, 2020 [PMID: 32183904](https://pubmed.ncbi.nlm.nih.gov/32183904/)",
"label": "PM1",
"ns": "070",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table\".",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113400",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113400",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--n"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS2_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "070",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual with full penetrance expected at an early age.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113397",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113397",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--E"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BS4_nuclear_SCN8A",
"additionalComments": "Reduced penetrance and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "070",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113394",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113394",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqW--_"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PS1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "The paralogous sodium channel genes associated with neurodevelomental disorders (SCN1A, SCN2A, SCN3A, SCN8A) share >77% sequence identity (PMID:33531663). The four homologous domains with voltage sensor and pore region remain largely preserved across the channels. Differences lie within the terminal regions and cytoplasmic loops. When these regions are excluded from analysis, homology increases to >90% (PMID:33531663; PMID:16382098). \n\nAs such, Pathogenic and Likely Pathogenic variants in paralogous genes can be considered for PS1.",
"label": "PS1",
"ns": "070",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n* **\\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).\n\n* A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113413",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113413",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS--D"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP7_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "070",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113404",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113404",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--F"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PVS1_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo nonsense-mediated decay: p.Thr1582\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "070",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. \n\nIn-frame exons: 1, 7, 8, 12, 17, 19, 25\n\nOut-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26\n\nTruncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113401",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113401",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS--A"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_BP1_nuclear_SCN8A",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "070",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113395",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113395",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpS---"
},
{
"created": "2024-03-19T18:43:30.166Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "070_PM4_nuclear_SCN8A",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN8A"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "070",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746113388",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746113388",
"modified": "2024-03-19T18:43:30.166Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--S"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962502623200,
"agr": "HGNC:10596",
"alias_symbol": [
"Nav1.6",
"NaCh6",
"PN4",
"CerIII",
"CIAT"
],
"ccds_id": [
"CCDS81692",
"CCDS44891",
"CCDS53794"
],
"date_approved_reserved": "1995-08-23",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
"ena": [
"AB027567"
],
"ensembl_gene_id": "ENSG00000196876",
"entrez_id": "6334",
"gene_group": [
"Sodium voltage-gated channel alpha subunits"
],
"gene_group_id": [
1203
],
"hgnc_id": "HGNC:10596",
"iuphar": "objectId:583",
"location": "12q13.13",
"location_sortable": "12q13.13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1389|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1389.xml"
],
"mane_select": [
"ENST00000627620.5",
"NM_001330260.2"
],
"mgd_id": [
"MGI:103169"
],
"name": "sodium voltage-gated channel alpha subunit 8",
"omim_id": [
"600702"
],
"orphanet": 293928,
"prev_name": [
"sodium channel, voltage gated, type VIII, alpha polypeptide",
"sodium channel, voltage gated, type VIII, alpha subunit",
"sodium channel, voltage gated, type VIII alpha subunit"
],
"prev_symbol": [
"MED"
],
"pubmed_id": [
7670495,
9828131,
16382098
],
"refseq_accession": [
"NM_014191"
],
"rgd_id": [
"RGD:3638"
],
"status": "Approved",
"symbol": "SCN8A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001ryw.4",
"uniprot_ids": [
"Q9UQD0"
],
"uuid": "a3c491dc-1846-4725-903d-2ab1d0eb4063",
"vega_id": "OTTHUMG00000169490"
}
},
"entId": "SCN8A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10596",
"entType": "Gene",
"ldhId": "467855399",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855399",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
"rev": "_h6SHz8q--V"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "070_nuclear_SCN8A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "Autosomal dominant germline de novo mutation (HP:0025352)",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "SCN8A",
"preferredTranscript": "NM_014191.4"
}
],
"ns": "070",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243147",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243147",
"modified": "2024-03-19T18:43:30.098Z",
"modifier": "laceysmith",
"rev": "_h6SHyTW--2"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Epilepsy SCN",
"approval": {
"step1": {
"approvalDate": "2021-09-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-04-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-18T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-03-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Epilepsy Sodium Channel",
"shortBaseName": "Epilepsy SCN",
"shortTitle": "Epilepsy Sodium Channel VCEP",
"title": "Epilepsy Sodium Channel Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50105",
"entIri": "http://clinicalgenome.org/affiliation/50105",
"entType": "Organization",
"ldhId": "639508904",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508904",
"modified": "2024-03-05T21:54:58.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--k"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243140",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243140",
"modified": "2024-03-19T18:43:30.042Z",
"modifier": "laceysmith",
"rev": "_h6SHykG--i"
},
{
"entContent": {
"approvedOn": "2023-10-05T13:24:37.478Z",
"description": "Hemophilia A",
"namespace": "GN071",
"releaseNotes": "Edits post SVI Review",
"shortTitle": "Coagulation Factor Deficiency Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-08-30T16:51:25.460Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-13T15:29:59.241Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-07T15:35:18.557Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-08T23:19:29.612Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-01T16:18:36.974Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-05T13:24:37.478Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"071"
],
"title": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN071",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP5_nuclear_F8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "071",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362908",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362908",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--H"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP6_nuclear_F8",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "071",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362907",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362907",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--T"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP1_nuclear_F8",
"additionalComments": "Not applicable for F8 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "071",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362887",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362887",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--G"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM1_nuclear_F8",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This rule is applicable to the variant residues noted above based on activity that is critical to the function of the factor VIII protein (PMID: 33592631, 35722946). Combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM1",
"ns": "071",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This code can be applied at the strong level for variants involving the following residues: R391-S392, R759-S760, E1701-Q1705, R1708-S1709, Y1683, Y1689, Y737, Y742.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code can be applied at the moderate level for variants involving the following residues: \n\nResidues affecting secretion: Arg1667, Arg1332\n\nFXa-binding residues: Gly2267-Gly2304 (with the exception of Ser2283)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362905",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--J"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP4_nuclear_F8",
"additionalComments": "Please use the PS4 code for probands meeting phenotype criteria.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia A phenotype requirements:** \n\\-Abnormal factor VIII activity levels in the severe range (\\< 1% factor VIII activity level) are sufficient to confer a diagnosis of hemophilia A. \n\\-If the proband's factor VIII level is in the mild or moderate range (1-40% factor VIII activity level) there must be a clear pattern of X-linked inheritance (i.e. - more than a sibling pair). \n\\-If the proband is in the mild/moderate range and is a simplex case, there are only affected siblings, or no family history information is available, documentation that von Willebrand disease (VWD) type 2N was ruled out as a diagnosis is required. If this documentation is not available, the two following exceptions can be made:\n\n1. If VWD 2N is ruled out in at least one proband, all other probands can be counted, OR\n2. If there are 4 or more unrelated probands reported with mild or moderate hemophilia A, all probands can be counted.\n\n\\-Full gene sequencing and deletion/duplication analysis of the _F8_ gene is required to use this rule code.\n\n\\-This rule code is not eligible for any variants meeting BA1 criteria.\n\n\\-A probands used for PP4 cannot be used for PS4.",
"label": "PP4",
"ns": "071",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Proband must meet hemophilia A phenotype criteria AND have full gene sequencing and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362904",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--F"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "PP3",
"ns": "071",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362902",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362902",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--E"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BP4",
"ns": "071",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.05.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362895",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--H"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PS3",
"ns": "071",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Abnormal factor VIII activity (\\<40 IU/dL or 40%) via one-stage or two-stage chromogenic assay in a cell line and/or mouse model.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent or significantly reduced factor VIII antigen levels compared to wildtype in a cell line by quantitative assay.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362894",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362894",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--R"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP3_nuclear_F8",
"additionalComments": "Not applicable for F8 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "071",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362893",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362893",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--Q"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo modified point system for a highly specific phenotype (see guidance below). Probands must meet the PS4 phenotype criteria to apply this code. Combine all assumed and confirmed de novo cases for this code and use at the appropriate strength based on amount of points for all probands.",
"label": "PS2",
"ns": "071",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362892",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362892",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--H"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM5_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM5",
"ns": "071",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on the _F8_ rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362886",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362886",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--O"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS3_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS3",
"ns": "071",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer a normal factor VIII activity level AND normal factor VIII antigen level OR normal Western Blot.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be used for _F8_ gene variants studied in a cell line or mouse model setting that confer the following results: \n\n* Normal factor VIII activity level, OR\n* Abnormal factor VIII activity level with abnormal 2N binding assay suggesting a diagnosis of VWD Normandy (VWD 2N) instead of hemophilia A.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362885",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362885",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--F"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This code is not applicable if there is a normal one stage factor VIII level and an abnormal factor VIII using a chromogenic assay or vice versa.",
"label": "BS2",
"ns": "071",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F8_ variant is observed in a male with a normal factor VIII activity level (\\<40% IU) using a one stage and/or a chromogenic assay.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362883",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362883",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--F"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP7_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Also applicable to non-canonical intronic variants. The use of BP7 with BP4 is allowed, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "071",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splice AI should be used to suggest no splicing impact. Splicing prediction score of less than or equal to 0.05 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362903",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362903",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--L"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP2_nuclear_F8",
"additionalComments": "Not applicable for F8.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "071",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362901",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362901",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--K"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM6_nuclear_F8",
"additionalComments": "This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "071",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362889",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362889",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--C"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": ".",
"label": "PM4",
"ns": "071",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362884",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362884",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--N"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM2_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "None",
"label": "PM2",
"ns": "071",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant must be absent in males in population databases, such as gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362906",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362906",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--G"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BA1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BA1",
"ns": "071",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of greater or equal to 0.0333% (or 0.000333).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362900",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362900",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--S"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP5_nuclear_F8",
"additionalComments": "While unlikely, it is possible for males with hemophilia to also have a diagnosis of von Willebrand Normandy (or VWD 2N).",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "071",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362899",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362899",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--J"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PVS1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Apply the ClinGen Coagulation Factor Deficiency VCEP/SVI decision tree to determine use and strength of the PVS1 rule.",
"label": "PVS1",
"ns": "071",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362898",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362898",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--I"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia A phenotype requirements:** \n\\-Abnormal factor VIII activity levels in the severe range (\\< 1% factor VIII activity level) are sufficient to confer a diagnosis of hemophilia A. \n\\-If the proband's factor VIII level is in the mild or moderate range (1-40% factor VIII activity level) there must be a clear pattern of X-linked inheritance (i.e. - more than a sibling pair). \n\\-If the proband is in the mild/moderate range and is a simplex case, there are only affected siblings, or no family history information is available, documentation that von Willebrand disease (VWD) type 2N was ruled out as a diagnosis is required. If this documentation is not available, the two following exceptions can be made:\n\n1. If VWD 2N is ruled out in at least one proband, all other probands can be counted, OR\n2. If there are 4 or more unrelated probands reported with mild or moderate hemophilia A, all probands can be counted.\n\n\\- _F8_ variants associated with severe and moderate disease severity are expected to be absent in males in population databases, such as gnomAD; however, this code can still be applied if a variant associated with mild hemophilia A if seen in 3 or less males. If the variant is seen in 3 males in population databases, the number of probands must meet a very strong weight for the PS4 code. If the variant is seen in 1-2 males in population databases, the number of probands must meet a strong weight in order to be applied.",
"label": "PS4",
"ns": "071",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥8 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 proband meets criteria described below",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362897",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--D"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BP2_nuclear_F8",
"additionalComments": "Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "071",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362891",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362891",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--P"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS4_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS4",
"ns": "071",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F8_ variant is observed in a male with a family history of hemophilia A and has a normal factor VIII activity level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362888",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362888",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--B"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PP1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "Base strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "071",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The code is application when there are ≥4 meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The code is application when there are at least 3 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The code is application when there are 2 meioses in one family **OR** 1 meiosis between 2 affected siblings.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362896",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--I"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PS1_nuclear_F8",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "071",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggesting a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362890",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362890",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpO--G"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_PM3_nuclear_F8",
"additionalComments": "Not applicable for the F8 gene.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "071",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362882",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362882",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--F"
},
{
"created": "2023-10-05T13:24:38.227Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "071_BS1_nuclear_F8",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F8"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BS1",
"ns": "071",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF cutoff of greater than or equal to 0.00333% (or 0.0000333).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620362881",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620362881",
"modified": "2023-10-05T13:24:38.227Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--E"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010602",
"lbl": "hemophilia A",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010602"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/factor_viii_deficiency"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hemophilia_a"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10016080"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/337607970"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/5501"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D006467"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/234440005"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0019069"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/D66"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12134"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C27146"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_98878"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/134500"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/306700"
}
],
"definition": {
"val": "The most common form of hemophilia characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency.",
"xrefs": [
"Orphanet:98878"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Subhemophilia",
"xrefs": [
"DOID:12134"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital factor VIII disorder",
"xrefs": [
"DOID:12134",
"ICD9CM:286.0",
"icd11.foundation:337607970"
]
},
{
"pred": "hasExactSynonym",
"val": "factor VIII deficiency",
"xrefs": [
"DOID:12134",
"MONDO:0007596",
"NCIT:C27146"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia a, X-linked recessive"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia type A"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia type a"
},
{
"pred": "hasExactSynonym",
"val": "hemophilia A",
"xrefs": [
"DOID:12134",
"MONDO:Lexical",
"NCIT:C27146",
"OMIM:306700",
"Orphanet:98878"
]
},
{
"pred": "hasExactSynonym",
"val": "hemophilia a, X-linked recessive"
},
{
"pred": "hasExactSynonym",
"val": "hemophilia type A",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hemophilia type a",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary Factor VIII deficiency",
"xrefs": [
"NCIT:C27146"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary Factor VIII deficiency disease",
"xrefs": [
"NCIT:C27146"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "HEMA",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Haemophilia A",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "autosomal haemophilia a"
},
{
"pred": "hasRelatedSynonym",
"val": "autosomal hemophilia a"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "classic haemophilia"
},
{
"pred": "hasRelatedSynonym",
"val": "classic hemophilia",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "classical haemophilia"
},
{
"pred": "hasRelatedSynonym",
"val": "classical hemophilia",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"val": "factor 8 deficiency",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia A, congenital"
},
{
"pred": "hasRelatedSynonym",
"val": "hem A",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"val": "hemophilia A, congenital",
"xrefs": [
"GARD:0006591"
]
},
{
"pred": "hasRelatedSynonym",
"val": "hemophilia, classic"
}
],
"xrefs": [
{
"val": "DOID:12134"
},
{
"val": "GARD:6591"
},
{
"val": "ICD10CM:D66"
},
{
"val": "ICD9:286.0"
},
{
"val": "MEDGEN:5501"
},
{
"val": "MESH:D006467"
},
{
"val": "MedDRA:10016080"
},
{
"val": "NANDO:2200676"
},
{
"val": "NCIT:C27146"
},
{
"val": "NORD:1221"
},
{
"val": "OMIM:134500"
},
{
"val": "OMIM:306700"
},
{
"val": "Orphanet:98878"
},
{
"val": "SCTID:234440005"
},
{
"val": "UMLS:C0019069"
},
{
"val": "icd11.foundation:337607970"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010602",
"name": "hemophilia A"
},
"entId": "MONDO:0010602",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010602",
"entType": "Disease",
"ldhId": "467893775",
"ldhIri": "https://genboree.org/cspec/Disease/id/467893775",
"modified": "2025-10-07T15:44:15.250Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WNYy---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056947221725200,
"agr": "HGNC:3546",
"alias_name": [
"Factor VIIIF8B",
"hemophilia A"
],
"alias_symbol": [
"FVIII",
"DXS1253E",
"HEMA"
],
"ccds_id": [
"CCDS35457",
"CCDS44026"
],
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-15",
"ena": [
"M90707"
],
"ensembl_gene_id": "ENSG00000185010",
"entrez_id": "2157",
"hgnc_id": "HGNC:3546",
"iuphar": "objectId:2607",
"location": "Xq28",
"location_sortable": "Xq28",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"HAMSTeRS: The Haemophilia A Mutation, Structure, Test & Resource Site|http://hadb.org.uk/",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/F8",
"LRG_555|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_555.xml"
],
"mane_select": [
"ENST00000360256.9",
"NM_000132.4"
],
"mgd_id": [
"MGI:88383"
],
"name": "coagulation factor VIII",
"omim_id": [
"300841"
],
"orphanet": 121677,
"prev_name": [
"coagulation factor VIII, procoagulant component"
],
"prev_symbol": [
"F8C"
],
"pubmed_id": [
6438528,
3935400
],
"refseq_accession": [
"NM_000132"
],
"rgd_id": [
"RGD:727845"
],
"status": "Approved",
"symbol": "F8",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004fmt.4",
"uniprot_ids": [
"P00451"
],
"uuid": "c5b3d83b-f5c3-42a6-8fdf-b46322126d35",
"vega_id": "OTTHUMG00000022688"
}
},
"entId": "F8",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3546",
"entType": "Gene",
"ldhId": "467825573",
"ldhIri": "https://genboree.org/cspec/Gene/id/467825573",
"modified": "2021-10-14T11:36:38.014Z",
"modifier": "genbadmin",
"rev": "_h6SHypO--K"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "071_nuclear_F8",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "primarily recessive with milder female expression",
"preferredModeOfInheritance": "X-linked inheritance",
"preferredMondoId": "MONDO:0010602",
"preferredTitle": "hemophilia A"
}
],
"gene": "F8",
"preferredTranscript": "NM_000132.4"
}
],
"ns": "071",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243148",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243148",
"modified": "2023-10-05T13:24:38.137Z",
"modifier": "leekristy",
"rev": "_h6SHyTW-_D"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CoagFactor",
"approval": {
"step1": {
"approvalDate": "2019-05-06T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-02-19T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-09-01T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-10-02T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Coagulation Factor Deficiency",
"shortBaseName": "CoagFactor",
"shortTitle": "Coagulation Factor Deficiency VCEP",
"title": "Coagulation Factor Deficiency Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50041",
"entIri": "http://clinicalgenome.org/affiliation/50041",
"entType": "Organization",
"ldhId": "639508881",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508881",
"modified": "2023-10-03T23:07:05.645Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--V"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243141",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243141",
"modified": "2023-10-05T13:24:38.065Z",
"modifier": "leekristy",
"rev": "_h6SHykS--R"
},
{
"entContent": {
"approvedOn": "2022-08-25T22:49:46.752Z",
"description": "",
"namespace": "GN072",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-07T19:39:10.992Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:32:59.443Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:34:41.999Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"072"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN072",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948748451800,
"agr": "HGNC:4584",
"alias_symbol": [
"GluN1"
],
"ccds_id": [
"CCDS43910",
"CCDS55355",
"CCDS7032",
"CCDS7031",
"CCDS55354"
],
"date_approved_reserved": "1992-09-18",
"date_modified": "2016-02-05",
"date_name_changed": "2016-02-05",
"ensembl_gene_id": "ENSG00000176884",
"entrez_id": "2902",
"gene_group": [
"Glutamate ionotropic receptor NMDA type subunits"
],
"gene_group_id": [
1201
],
"hgnc_id": "HGNC:4584",
"iuphar": "objectId:455",
"location": "9q34.3",
"location_sortable": "09q34.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000371561.8",
"NM_007327.4"
],
"mgd_id": [
"MGI:95819"
],
"name": "glutamate ionotropic receptor NMDA type subunit 1",
"omim_id": [
"138249"
],
"orphanet": 282786,
"prev_name": [
"N-methyl-D-aspartate receptor subunit NR1",
"glutamate receptor, ionotropic, N-methyl D-aspartate 1"
],
"prev_symbol": [
"NMDAR1"
],
"pubmed_id": [
1350383
],
"refseq_accession": [
"NM_007327"
],
"rgd_id": [
"RGD:2736"
],
"status": "Approved",
"symbol": "GRIN1",
"ucsc_id": "uc004cln.4",
"uniprot_ids": [
"Q05586"
],
"uuid": "72f60496-de13-49e9-950d-6c4d6bdc8a8f",
"vega_id": "OTTHUMG00000020976"
}
},
"entId": "GRIN1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4584",
"entType": "Gene",
"ldhId": "467828347",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828347",
"modified": "2021-10-14T11:36:40.845Z",
"modifier": "genbadmin",
"rev": "_h6SHysS--B"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "072_nuclear_GRIN1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "GRIN1",
"preferredTranscript": "NM_007327.3"
}
],
"ns": "072",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243149",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243149",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--c"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "GRIN",
"approval": {
"step1": {
"approvalDate": "2020-08-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approved": false
},
"step3": {
"approved": false
},
"step4": {
"approved": false
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "GRIN Disorders ",
"shortBaseName": "GRIN",
"shortTitle": "GRIN Disorders VCEP",
"title": "GRIN Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50078",
"entIri": "http://clinicalgenome.org/affiliation/50078",
"entType": "Organization",
"ldhId": "639508892",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508892",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243142",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243142",
"modified": "2023-04-11T17:34:42.193Z",
"modifier": "sharriso",
"rev": "_h6SHykC--D"
},
{
"entContent": {
"description": "",
"namespace": "GN073",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T13:45:57.209Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:34:49.731Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:36:09.282Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"073"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2A Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN073",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0017325",
"lbl": "early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9063"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/early_onset_epileptic_encephalopathy_and_intellectual_disability_due_to_grin2a_mutation"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1655554340"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1663334"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C4749281"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_289266"
}
],
"definition": {
"val": "A rare intellectual disability and epilepsy syndrome due to mutation in GRIN2A gene. It is characterized by global developmental delay and mild to profound intellectual disability, multiple types of usually intractable focal and generalized seizures with variable abnormal EEG findings, and bilateral progressive parenchymal volume loss and thin corpus callosum on brain MRI.",
"xrefs": [
"Orphanet:289266"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation",
"xrefs": [
"Orphanet:289266",
"icd11.foundation:1655554340"
]
},
{
"pred": "hasExactSynonym",
"val": "epilepsy, focal, with speech disorder and with or without impaired intellectual development",
"xrefs": [
"OMIM:245570",
"Orphanet:289266"
]
}
],
"xrefs": [
{
"val": "GARD:21134"
},
{
"val": "MEDGEN:1663334"
},
{
"val": "OMIM:613971"
},
{
"val": "Orphanet:289266"
},
{
"val": "UMLS:C4749281"
},
{
"val": "icd11.foundation:1655554340"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0017325",
"name": "early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation"
},
"entId": "MONDO:0017325",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0017325",
"entType": "Disease",
"ldhId": "467897404",
"ldhIri": "https://genboree.org/cspec/Disease/id/467897404",
"modified": "2025-10-07T15:46:07.552Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7X7Jm---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948748451800,
"agr": "HGNC:4585",
"alias_symbol": [
"GluN2A"
],
"ccds_id": [
"CCDS10539",
"CCDS45407"
],
"cosmic": "GRIN2A",
"date_approved_reserved": "1992-09-18",
"date_modified": "2016-02-05",
"date_name_changed": "2016-02-05",
"ensembl_gene_id": "ENSG00000183454",
"entrez_id": "2903",
"gene_group": [
"Glutamate ionotropic receptor NMDA type subunits"
],
"gene_group_id": [
1201
],
"hgnc_id": "HGNC:4585",
"iuphar": "objectId:456",
"location": "16p13.2",
"location_sortable": "16p13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000330684.4",
"NM_001134407.3"
],
"mgd_id": [
"MGI:95820"
],
"name": "glutamate ionotropic receptor NMDA type subunit 2A",
"omim_id": [
"138253"
],
"orphanet": 289276,
"prev_name": [
"glutamate receptor, ionotropic, N-methyl D-aspartate 2A"
],
"prev_symbol": [
"NMDAR2A"
],
"pubmed_id": [
9480759
],
"refseq_accession": [
"NM_000833"
],
"rgd_id": [
"RGD:2737"
],
"status": "Approved",
"symbol": "GRIN2A",
"ucsc_id": "uc010uym.3",
"uniprot_ids": [
"Q12879"
],
"uuid": "ffd7bb89-cd0d-49b4-aba4-f40c07586204",
"vega_id": "OTTHUMG00000129721"
}
},
"entId": "GRIN2A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4585",
"entType": "Gene",
"ldhId": "467828348",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828348",
"modified": "2021-10-14T11:36:40.845Z",
"modifier": "genbadmin",
"rev": "_h6SHyq6--P"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "073_nuclear_GRIN2A",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "GRIN2A",
"preferredTranscript": "NM_001134407.2"
}
],
"ns": "073",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243150",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243150",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--U"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "GRIN",
"approval": {
"step1": {
"approvalDate": "2020-08-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approved": false
},
"step3": {
"approved": false
},
"step4": {
"approved": false
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "GRIN Disorders ",
"shortBaseName": "GRIN",
"shortTitle": "GRIN Disorders VCEP",
"title": "GRIN Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50078",
"entIri": "http://clinicalgenome.org/affiliation/50078",
"entType": "Organization",
"ldhId": "639508892",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508892",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243143",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243143",
"modified": "2023-04-11T17:36:09.541Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--_"
},
{
"entContent": {
"description": "",
"namespace": "GN074",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T14:02:11.437Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:35:56.462Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:36:54.577Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"074"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2B Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN074",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0035122",
"lbl": "GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5588"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9063"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0006012",
"val": "2025-09-01"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/grin2b_related_developmental_delay_intellectual_disability_and_autism_spectrum_disorder"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0000508"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1830118"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5681638"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_589547"
}
],
"comments": [
"This term is scheduled to be merged with MONDO:0013509 intellectual disability, autosomal dominant 6. This ID will therefore be obsoleted and replaced with MONDO:0013509"
],
"definition": {
"val": "A rare genetic syndromic intellectual disability in which the cause of the disease is a variation in the GRIN2B gene. It is characterized by infantile or childhood onset of mild to profound developmental delay and intellectual disability in all affected individuals, as well as variable occurrence of epilepsy, autism spectrum disorder / behavioral issues, microcephaly, muscle tone abnormalities such as hypotonia and spasticity, dystonic, dyskinetic, or choreiform movement disorder, and cortical visual impairment. Brain MRI may reveal abnormal cortical development, hypoplastic corpus callosum, enlarged/dysplastic basal ganglia, and hippocampal dysplasia.",
"xrefs": [
"Orphanet:589547"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#obsoletion_candidate",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "GRIN2B encephalopathy",
"xrefs": [
"PMID:29851452",
"https://orcid.org/0000-0001-9310-0163"
]
},
{
"pred": "hasBroadSynonym",
"val": "GRIN2B-related neurodevelopmental disorder",
"xrefs": [
"Orphanet:589547",
"PMID:29851452",
"https://orcid.org/0000-0001-9310-0163"
]
}
],
"xrefs": [
{
"val": "GARD:22356"
},
{
"val": "MEDGEN:1830118"
},
{
"val": "Orphanet:589547"
},
{
"val": "UMLS:C5681638"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0035122",
"name": "GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder"
},
"entId": "MONDO:0035122",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0035122",
"entType": "Disease",
"ldhId": "467888664",
"ldhIri": "https://genboree.org/cspec/Disease/id/467888664",
"modified": "2025-10-07T15:48:04.139Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7ZtQS---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948749500400,
"agr": "HGNC:4586",
"alias_symbol": [
"GluN2B"
],
"ccds_id": [
"CCDS8662"
],
"date_approved_reserved": "1992-09-18",
"date_modified": "2016-02-05",
"date_name_changed": "2016-02-05",
"ensembl_gene_id": "ENSG00000273079",
"entrez_id": "2904",
"gene_group": [
"Glutamate ionotropic receptor NMDA type subunits"
],
"gene_group_id": [
1201
],
"hgnc_id": "HGNC:4586",
"iuphar": "objectId:457",
"location": "12p13.1",
"location_sortable": "12p13.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000609686.4",
"NM_000834.5"
],
"mgd_id": [
"MGI:95821"
],
"name": "glutamate ionotropic receptor NMDA type subunit 2B",
"omim_id": [
"138252"
],
"orphanet": 266126,
"prev_name": [
"glutamate receptor, ionotropic, N-methyl D-aspartate 2B"
],
"prev_symbol": [
"NMDAR2B"
],
"pubmed_id": [
1350383
],
"refseq_accession": [
"NM_000834"
],
"rgd_id": [
"RGD:2738"
],
"status": "Approved",
"symbol": "GRIN2B",
"ucsc_id": "uc001rbt.3",
"uniprot_ids": [
"Q13224"
],
"uuid": "2797e1fc-197f-4870-895d-9a7d19cd3de9",
"vega_id": "OTTHUMG00000137373"
}
},
"entId": "GRIN2B",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4586",
"entType": "Gene",
"ldhId": "467828349",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828349",
"modified": "2021-10-14T11:36:40.845Z",
"modifier": "genbadmin",
"rev": "_h6SHysS--C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "074_nuclear_GRIN2B",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "GRIN2B",
"preferredTranscript": "NM_000834.3"
}
],
"ns": "074",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243151",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243151",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--W"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "GRIN",
"approval": {
"step1": {
"approvalDate": "2020-08-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approved": false
},
"step3": {
"approved": false
},
"step4": {
"approved": false
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "GRIN Disorders ",
"shortBaseName": "GRIN",
"shortTitle": "GRIN Disorders VCEP",
"title": "GRIN Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50078",
"entIri": "http://clinicalgenome.org/affiliation/50078",
"entType": "Organization",
"ldhId": "639508892",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508892",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243144",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243144",
"modified": "2023-04-11T17:36:54.940Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--A"
},
{
"entContent": {
"description": "",
"namespace": "GN075",
"releaseNotes": "",
"shortTitle": "GRIN Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-08T15:02:00.319Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-01-16T13:36:34.270Z"
},
"name": "Classification Rules Submitted"
},
{
"current": true,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-11T17:37:05.831Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"075"
],
"title": "ClinGen GRIN Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GRIN2D Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN075",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100038",
"lbl": "complex neurodevelopmental disorder",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7308"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100038"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/non_specific_syndromic_intellectual_disability"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019117"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-06-29T18:21:11Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1800189"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5568766"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_528084"
}
],
"definition": {
"val": "A disorder that involves more than one phenotype associated with the central nervous system, including but not limited to intellectual disability, autism, and seizures (epilepsy).",
"xrefs": [
"https://orcid.org/0000-0002-6733-369X",
"https://www.clinicalgenome.org/working-groups/clinical-domain/neurodevelopmental-disorders/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "complex neurodevelopmental disorder",
"xrefs": [
"Orphanet:528084"
]
}
],
"xrefs": [
{
"val": "GARD:17965"
},
{
"val": "MEDGEN:1800189"
},
{
"val": "Orphanet:528084"
},
{
"val": "UMLS:C5568766"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100038",
"name": "complex neurodevelopmental disorder"
},
"entId": "MONDO:0100038",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100038",
"entType": "Disease",
"ldhId": "467881646",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881646",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFjC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948750549000,
"agr": "HGNC:4588",
"alias_name": [
"N-methyl-d-aspartate receptor subunit 2D"
],
"alias_symbol": [
"GluN2D",
"EB11",
"NR2D"
],
"ccds_id": [
"CCDS12719"
],
"date_approved_reserved": "1993-07-29",
"date_modified": "2016-02-05",
"date_name_changed": "2016-02-05",
"ena": [
"U77783"
],
"ensembl_gene_id": "ENSG00000105464",
"entrez_id": "2906",
"gene_group": [
"Glutamate ionotropic receptor NMDA type subunits"
],
"gene_group_id": [
1201
],
"hgnc_id": "HGNC:4588",
"iuphar": "objectId:459",
"location": "19q13.33",
"location_sortable": "19q13.33",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000263269.4",
"NM_000836.4"
],
"mgd_id": [
"MGI:95823"
],
"name": "glutamate ionotropic receptor NMDA type subunit 2D",
"omim_id": [
"602717"
],
"orphanet": 469057,
"prev_name": [
"glutamate receptor, ionotropic, N-methyl D-aspartate 2D"
],
"prev_symbol": [
"NMDAR2D"
],
"pubmed_id": [
9480759,
9418891
],
"refseq_accession": [
"NM_000836"
],
"rgd_id": [
"RGD:2740"
],
"status": "Approved",
"symbol": "GRIN2D",
"ucsc_id": "uc002pjc.4",
"uniprot_ids": [
"O15399"
],
"uuid": "a38e4d9e-50de-4555-8294-134c13856e2f",
"vega_id": "OTTHUMG00000183304"
}
},
"entId": "GRIN2D",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4588",
"entType": "Gene",
"ldhId": "467828351",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828351",
"modified": "2021-10-14T11:36:40.845Z",
"modifier": "genbadmin",
"rev": "_h6SHysS--G"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "075_nuclear_GRIN2D",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0100038",
"preferredTitle": "complex neurodevelopmental disorder"
}
],
"gene": "GRIN2D",
"preferredTranscript": "NM_000836.4"
}
],
"ns": "075",
"references": []
},
"entType": "RuleSet",
"ldhId": "643243152",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243152",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--n"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "GRIN",
"approval": {
"step1": {
"approvalDate": "2020-08-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approved": false
},
"step3": {
"approved": false
},
"step4": {
"approved": false
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "GRIN Disorders ",
"shortBaseName": "GRIN",
"shortTitle": "GRIN Disorders VCEP",
"title": "GRIN Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50078",
"entIri": "http://clinicalgenome.org/affiliation/50078",
"entType": "Organization",
"ldhId": "639508892",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508892",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--S"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243145",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243145",
"modified": "2023-04-11T17:37:06.024Z",
"modifier": "sharriso",
"rev": "_h6SHyjy--B"
},
{
"entContent": {
"approvedOn": "2024-03-19T18:38:47.541Z",
"description": "SCN1B",
"namespace": "GN076",
"releaseNotes": "",
"shortTitle": "Epilepsy Sodium Channel Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-12T19:49:49.841Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-17T20:00:33.365Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-10-22T15:35:43.650Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-04-22T14:47:34.421Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "laceysmith",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-01-11T22:06:05.714Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-08T23:01:49.182Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-26T23:04:29.860Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "laceysmith",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-03-19T18:38:47.541Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"076"
],
"title": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN076",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BS1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BS1",
"ns": "076",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Allele frequency is above **0.01%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109680",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109680",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--S"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM6_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "076",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109676",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109676",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--D"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BS3_nuclear_SCN1B",
"additionalComments": "Cellular electrophysiology (voltage clamp recording): Values indicating “no impact on channel function” have not been sufficiently characterized to date. Additionally, one cannot exclude non-electrophysiological defects such as mis-localization in a neuron based solely on heterologous expression studies. \nThis can be re-assessed by the EP over time and as benign variants are functionally characterized in the future.\n\nAnimal Models: Lack of an epilepsy phenotype in an animal model is insufficient to support benignity of a variant. Additionally, some non-epilepsy co-morbidities, such as behavioral characteristics that may mimic intellectual disability and/or autism spectrum disorder, are still being established and could support pathogenicity. \nThis can be re-assessed by the EP over time. \n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "076",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109666",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109666",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--H"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM2_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "076",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109662",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109662",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--O"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS1",
"ns": "076",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.\n\nSame predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).\n\n* PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (\"PS1\\_Variants impacting splicing\").",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109686",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109686",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--V"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP3_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "076",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "In frame-deletions/insertions in a repetitive region without a known function.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109683",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109683",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--T"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP7_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "076",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109677",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109677",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--E"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BS2_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "076",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Observed in a healthy adult individual.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109670",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109670",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--B"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM5_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "076",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This should say greater than or equal to 2 known pathogenic variants at same site as novel change.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.\n\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Novel missense change at an amino acid residue where a different missense change determined to be **Likely Pathogenic** has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109665",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109665",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpK--P"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP4_nuclear_SCN1B",
"additionalComments": "Replicating methodologies by Pejaver et al, 2022 and Johnston et al, 2021 (PMID: 33767344), REVEL scores could not be obtained for Benign calculations. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "076",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109688",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109688",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO--_"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP6_nuclear_SCN1B",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "076",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109687",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109687",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--F"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "076",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members\n\nAD: ≥7 independent meioses\n\nAR: ≥3 affected segregations",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members\n\nAD: 5-6 independent meioses\n\nAR: 2 affected segregations",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members\n\nAD: 3-4 independent meioses\n\nAR: 1 affected segregation",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109682",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109682",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpK--R"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS3_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "076",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Mouse knock-in model displays spontaneous seizures.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "* Heterologous expression with voltage clamping shows statistically significant difference over wildtype in at least one parameter (https://bioportal.bioontology.org/ontologies/FENICS)\n* Mouse knock-in model displays induced seizures\n* Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109679",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109679",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpK--Q"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP1_nuclear_SCN1B",
"additionalComments": "Missense variants are common cause of disease. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "076",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109668",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109668",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--P"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BS4_nuclear_SCN1B",
"additionalComments": "Reduced penetrance, variable expressivity and phenocopies",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "076",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Not applicable",
"id": "0071",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0077",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109667",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109667",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--A"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS2_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "076",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1 point** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **0.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points\n\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109685",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109685",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--U"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP4_nuclear_SCN1B",
"additionalComments": "Phenotypic specificity incorporated into PS2, PM6, PS4",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "076",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109684",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109684",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpO---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP5_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "076",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Variant found in a case with an alternate molecular basis for disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109681",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109681",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqO---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP3_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP3",
"ns": "076",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Follow ClinGen’s recommendations ([PMID: 36413997](https://pubmed.ncbi.nlm.nih.gov/36413997/)), using REVEL as the computational tool, with the following stipulations:\n\n1. Strength should be capped at Moderate, and \n2. limit the combination of PP3 and PM1 to reach no higher than strong",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109678",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109678",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG--_"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BA1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "076",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Allele frequency is above **0.3%** in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109675",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109675",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--C"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PVS1_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "Most terminal codon expected to undergo NMD: p.Thr204\n\nFor splice sites, this criterion should not be applied with PP3. \n\nFor a full gene deletion, a pathogenic classification is warranted.",
"label": "PVS1",
"ns": "076",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.**\n\nMost terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. \n\nIn-frame exons: 3-5\n\nOut-of-frame exons: 1-2\n\nFor splice region variants, this criterion should not be applied with PP3.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109674",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109674",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--R"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM3_nuclear_SCN1B",
"additionalComments": "SCN1A is associated with autosomal dominant inheritance. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "076",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **4.0 points** will arrive at **Very Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **2.0 points** will arrive at **Strong**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **1.0 point** will arrive at **Moderate**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of **0.5 points** will arrive at **Supporting**. \n\n* Classification of other variant is Pathogenic/Likely Pathogenic\n * Confirmed in trans: 1 point\n * Phase unknown: 0.5 (P) or 0.25 (LP) points\n* Homozygous occurrence (max point 1.0)\n * Confirmed in trans: 0.5 points\n* Classification of other variant is Uncertain Significance \n * Confirmed in trans: 0.25 points\n * Phase unknown: 0 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109672",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109672",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--I"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP5_nuclear_SCN1B",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "076",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109671",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109671",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpy--Q"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM4_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "076",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109661",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109661",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqK--G"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PM1_nuclear_SCN1B",
"additionalComments": "Currently, insufficient numbers of pathogenic variants have been reported in SCN1B to calculate “mutational hotspots”. SCN1B does not belong to a gene family to utilize PERs.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "076",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109673",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109673",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqG---"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PP2_nuclear_SCN1B",
"additionalComments": "Benign missense variants are common. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "076",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109669",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109669",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqC--K"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_BP2_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "076",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109664",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109664",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxqC--J"
},
{
"created": "2024-03-19T18:38:48.195Z",
"creator": "laceysmith",
"entContent": {
"_uniqueProp": "076_PS4_nuclear_SCN1B",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SCN1B"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "076",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **16+ points** will arrive at **Very Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4-15.5 points** will arrive at **Strong**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2-3.5 points** will arrive at **Moderate**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of **1-1.5 points** will arrive at **Supporting**. \n\nGenetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point\n\nOther epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1746109663",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1746109663",
"modified": "2024-03-19T18:38:48.195Z",
"modifier": "laceysmith",
"rev": "_h6SHxpm--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0100062",
"lbl": "genetic developmental and epileptic encephalopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/19"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/3680"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8274"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0100062"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/developmental_and_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/early_infantile_epileptic_encephalopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015921"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0024321"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100022"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://purl.org/dc/elements/1.1/date",
"val": "2018-10-10T22:04:15Z"
},
{
"pred": "http://purl.org/dc/terms/creator",
"val": "https://orcid.org/0000-0001-5208-3432"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0112202"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C122814"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS308350"
}
],
"comments": [
"Individuals, both male and female, have been reported with variants in the GABRB3 gene. De novo and familial cases have been reported, with mostly missense and a few nonsense variants identified as causative. These patients have been described in the literature as having a range of phenotypes characterized as epileptic encephalopathy, Lennox-Gastaut syndrome, Dravet syndrome-like, and childhood absence epilepsy. Severity of intellectual disability is variable among reported probands, as is the age of onset of seizure phenotypes. In one case of epileptic encephalopathy, for example, the individual presented with severe intellectual disability while seizures onset at 12 years old. Additionally, individuals have been reported with the same de novo missense variants, and have been described with varying phenotypes. (PMID:26544041, PMID:26704558, PMID:26645412, PMID:26993267, PMID:27476654)"
],
"definition": {
"val": "A complex neurodevelopmental disorder characterized by a range of developmental delays and epileptic encephalopathy phenotypes. Seizure onset is variable and intellectual disability is variable in presence and severity.",
"xrefs": [
"PMID:28276062"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "developmental and epileptic encephalopathy",
"xrefs": [
"DOID:0112202",
"NCIT:C122814",
"OMIMPS:308350",
"https://orcid.org/0000-0001-8486-0558"
]
},
{
"pred": "hasNarrowSynonym",
"val": "hereditary developmental and epileptic encephalopathy",
"xrefs": [
"https://orcid.org/0000-0001-5208-3432"
]
}
],
"xrefs": [
{
"val": "DOID:0112202"
},
{
"val": "GARD:9255"
},
{
"val": "ICD9:345.10"
},
{
"val": "NANDO:1200593"
},
{
"val": "NCIT:C122814"
},
{
"val": "OMIMPS:308350"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0100062",
"name": "genetic developmental and epileptic encephalopathy"
},
"entId": "MONDO:0100062",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0100062",
"entType": "Disease",
"ldhId": "467881472",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881472",
"modified": "2025-10-07T15:48:29.356Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7aFoe--D"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018214",
"lbl": "generalized epilepsy with febrile seizures plus",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5957"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/7924"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8280"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0018214"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/generalized_epilepsy_with_febrile_seizures_plus"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0005579"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://www.epilepsydiagnosis.org/syndrome/fbp-overview.html"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/503203"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C565808"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/699688008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3502809"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060170"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C122811"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_36387"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS604233"
}
],
"definition": {
"val": "A familial epilepsy syndrome in which family members display a seizure disorder from the generalized epilepsy with febrile seizures plus spectrum which ranges from simple febrile seizures (FS) to the more severe phenotype of myoclonic-astatic epilepsy (MAE) or Dravet syndrome (DS).",
"xrefs": [
"Orphanet:36387"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "GEFS+",
"xrefs": [
"DOID:0060170",
"NCIT:C122811",
"Orphanet:36387"
]
},
{
"pred": "hasExactSynonym",
"val": "epilepsy, generalized, with febrile seizures plus",
"xrefs": [
"OMIMPS:604233"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "generalised epilepsy with febrile seizures-plus"
},
{
"pred": "hasExactSynonym",
"val": "generalized epilepsy with febrile seizures plus",
"xrefs": [
"DOID:0060170",
"NCIT:C122811",
"https://www.clinicalgenome.org/affiliation/40005/"
]
},
{
"pred": "hasExactSynonym",
"val": "genetic epilepsy with febrile seizures plus",
"xrefs": [
"https://www.clinicalgenome.org/affiliation/40005/",
"https://www.epilepsydiagnosis.org/syndrome/fbp-overview.html"
]
},
{
"pred": "hasExactSynonym",
"val": "genetic epilepsy with febrile seizures-plus",
"xrefs": [
"Orphanet:36387",
"https://www.clinicalgenome.org/affiliation/40005/"
]
}
],
"xrefs": [
{
"val": "DOID:0060170"
},
{
"val": "GARD:18641"
},
{
"val": "MEDGEN:503203"
},
{
"val": "MESH:C565808"
},
{
"val": "NCIT:C122811"
},
{
"val": "OMIMPS:604233"
},
{
"val": "Orphanet:36387"
},
{
"val": "SCTID:699688008"
},
{
"val": "UMLS:C3502809"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018214",
"name": "generalized epilepsy with febrile seizures plus"
},
"entId": "MONDO:0018214",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018214",
"entType": "Disease",
"ldhId": "467877022",
"ldhIri": "https://genboree.org/cspec/Disease/id/467877022",
"modified": "2025-10-07T15:46:23.439Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YKnu---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962495283200,
"agr": "HGNC:10586",
"ccds_id": [
"CCDS12441",
"CCDS46047",
"CCDS86744"
],
"date_approved_reserved": "1990-05-14",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-05",
"ensembl_gene_id": "ENSG00000105711",
"entrez_id": "6324",
"gene_group": [
"V-set domain containing",
"Sodium voltage-gated channel beta subunits"
],
"gene_group_id": [
590,
1204
],
"hgnc_id": "HGNC:10586",
"location": "19q13.11",
"location_sortable": "19q13.11",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_420|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_420.xml"
],
"mane_select": [
"ENST00000262631.11",
"NM_001037.5"
],
"mgd_id": [
"MGI:98247"
],
"name": "sodium voltage-gated channel beta subunit 1",
"omim_id": [
"600235"
],
"orphanet": 118498,
"prev_name": [
"sodium channel, voltage-gated, type I, beta polypeptide",
"sodium channel, voltage-gated, type I, beta",
"sodium channel, voltage-gated, type I, beta subunit",
"sodium channel, voltage gated, type I beta subunit"
],
"pubmed_id": [
8394762
],
"refseq_accession": [
"NM_001037"
],
"rgd_id": [
"RGD:3631"
],
"status": "Approved",
"symbol": "SCN1B",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002nxp.4",
"uniprot_ids": [
"Q07699"
],
"uuid": "b990b0e4-857f-4020-a61b-152b638bcbfe",
"vega_id": "OTTHUMG00000182472"
}
},
"entId": "SCN1B",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10586",
"entType": "Gene",
"ldhId": "467855390",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855390",
"modified": "2021-10-14T11:37:07.088Z",
"modifier": "genbadmin",
"rev": "_h6SHz8q--p"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "076_nuclear_SCN1B",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "Other",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0018214",
"preferredTitle": "generalized epilepsy with febrile seizures plus"
},
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0100062",
"preferredTitle": "developmental and epileptic encephalopathy"
}
],
"gene": "SCN1B",
"preferredTranscript": "NM_001037.4"
}
],
"ns": "076",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PM6_Strong",
"PP1_Strong",
"PP3_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM3",
"PM4",
"PM5",
"PM6",
"PP1_Moderate",
"PP3_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP2",
"BP3",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "643243153",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/643243153",
"modified": "2024-03-19T18:38:48.120Z",
"modifier": "laceysmith",
"rev": "_h6SHyTW--w"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Epilepsy SCN",
"approval": {
"step1": {
"approvalDate": "2021-09-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-04-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-18T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-03-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Epilepsy Sodium Channel",
"shortBaseName": "Epilepsy SCN",
"shortTitle": "Epilepsy Sodium Channel VCEP",
"title": "Epilepsy Sodium Channel Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50105",
"entIri": "http://clinicalgenome.org/affiliation/50105",
"entType": "Organization",
"ldhId": "639508904",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508904",
"modified": "2024-03-05T21:54:58.523Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--k"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "643243146",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/643243146",
"modified": "2024-03-19T18:38:48.061Z",
"modifier": "laceysmith",
"rev": "_h6SHykK--N"
},
{
"entContent": {
"approvedOn": "2023-11-28T19:22:51.081Z",
"description": "Summary of ACMG-AMP Criteria for PALB2 associated with hereditary breast and pancreatic cancer",
"namespace": "GN077",
"releaseNotes": "Version 1.1 updates \nUpdated PS1 table to match Splicing SVI recommendations (PMID: 37352859) \nCorrected errors in verbiage/typos for BP4 \nChanged BP4 from not applicable to applicable to make application of BP4 for splicing more visible in CSPEC \nVerbiage update: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing \\[updated from error in typing that said shows impact\\] \nVerbiage update: \\*NOTE: BP4 splice predictions may not be used in conjunction with BP7\\_variable (RNA) \\[updated from just BP7 for clarification\\]. \nAdded BP4 under the combinations for Benign and LB classification \\[this was omitted in error\\]",
"releasedUnderRevision": true,
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-19T19:40:21.917Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-17T16:41:21.334Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-01-04T19:06:13.746Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-20T16:56:25.278Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-28T19:18:26.994Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-28T19:22:51.081Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-17T16:21:04.033Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"077"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN077",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "077_BP6_nuclear_PALB2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "077",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584518",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584518",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxq---_"
},
{
"entContent": {
"_uniqueProp": "077_BP5_nuclear_PALB2",
"additionalComments": "Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "077",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584517",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584517",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--L"
},
{
"entContent": {
"_uniqueProp": "077_BP1_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2.",
"label": "BP1",
"ns": "077",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": " Apply to all missense variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584513",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584513",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--D"
},
{
"entContent": {
"_uniqueProp": "077_BS3_nuclear_PALB2",
"additionalComments": "●\tDo not use: Protein functional studies (BS3) See PS3 for details \n●\tRNA functional studies (Use BP7_Variable(RNA))",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).",
"label": "BS3",
"ns": "077",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General Recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General Recommendation",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584511",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584511",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--G"
},
{
"entContent": {
"_uniqueProp": "077_BS2_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* See Fanconi Anemia BS2 tables\n* Do not use for individuals in population based cohorts, such as gnomAD \n* Consider multiple instances of co-occurrence with the same variant are more likely to be in cis in unrelated individuals when assessing BS2 application",
"label": "BS2",
"ns": "077",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Per Fanconi Anemia BS2 tables",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Per Fanconi Anemia BS2 tables",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Per Fanconi Anemia BS2 tables",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584510",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584510",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxq----"
},
{
"entContent": {
"_uniqueProp": "077_BS1_nuclear_PALB2",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Rounded from .0118% established using Whiffin calculator[10](#url_43417751-122f-5902-830e-7d96b15a14c6): \n * Prevalence (breast cancer): 8 \n * Allelic Heterogeneity: 0.1 (differs from BA1) \n * Genetic Heterogeneity: .01 \n * Penetrance: .53",
"label": "BS1",
"ns": "077",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD **Filtering Allele Frequency** greater than expected for disease\n\n**\\>.01%**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584509",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584509",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--L"
},
{
"entContent": {
"_uniqueProp": "077_PP4_nuclear_PALB2",
"additionalComments": "Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.\nFor AR disorder, use PM3 for specific phenotype considerations\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "077",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584506",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584506",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--I"
},
{
"entContent": {
"_uniqueProp": "077_PM6_nuclear_PALB2",
"additionalComments": "Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "077",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584502",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584502",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--A"
},
{
"entContent": {
"_uniqueProp": "077_PM2_nuclear_PALB2",
"additionalComments": "PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* PM2\\_supporting is not considered a conflicting piece of evidence for variants that otherwise are likely benign/benign \n* Use as PM2\\_Supporting (not moderate)",
"label": "PM2",
"ns": "077",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant absent in gnomAD or present in ≤ 1/300,000 alleles",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584498",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584498",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--B"
},
{
"entContent": {
"_uniqueProp": "077_PM1_nuclear_PALB2",
"additionalComments": "Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "077",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584497",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584497",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--A"
},
{
"entContent": {
"_uniqueProp": "077_PS4_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "PS4_Moderate: Do not use. Proband counting for genes causing a common disorder need to be calibrated in a population-specific way before use. \n",
"label": "PS4",
"ns": "077",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584496",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584496",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--_"
},
{
"entContent": {
"_uniqueProp": "077_BA1_nuclear_PALB2",
"additionalComments": "FAF is a statistical model that accounts for population size and founder populations.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Rounded from .118% established using Whiffin calculator[10](#url_43417751-122f-5902-830e-7d96b15a14c6):\n\n* Prevalence (breast cancer): 1:8\n* Allelic Heterogeneity: 1 (differs from BS1)\n* Genetic Heterogeneity: .01\n* Penetrance: .53",
"label": "BA1",
"ns": "077",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD **Filtering Allele Frequency** Allele frequency\n\n**\\>0.1%**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584508",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584508",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--C"
},
{
"entContent": {
"_uniqueProp": "077_PP1_nuclear_PALB2",
"additionalComments": "Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* AD Condition: use as per Co-Segregation Guidelines\n* AR Condition: informative instances of co-segregation in FANCN families are too rare to be considered for weight at this time. \n* Co-Segregation Guidelines\n * Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores[9](#pmid_29300386) using multiple phenotypes.\n * PP1\\_Strong: LOD ≥1.26 or Bayes Factor (LR) ≥18:1\n * PP1\\_Moderate: LOD ≥.60 or Bayes Factor (LR) ≥4:1\n * PP1: LOD ≥0.3 or Bayes Factor (LR) ≥2:18\n * BS4\\_Supporting: LOD ≤-.32 or Bayes Factor (LR) ≤.48\n * BS4\\_Moderate: LOD ≤ -.64 or Bayes Factor (LR) ≤.23\n * BS4: LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1\n* A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng’s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1\\. Navigate to COOL (COsegregation OnLine)[7](#url_5e582422-7218-5d1c-9887-88a8dd6ac60f) \n 2\\. Input ‘PALB2’ into the ‘Input a Gene Symbol’ field (the PALB2 defaults are approved by this VCEP) \n 3\\. Upload your Pedigree File (see COOL (COsegregation OnLine) manual[8](#url_5d379a36-2cd8-5961-a6fc-7ce50795ce00) for formatting) \n 4\\. Leave all defaults as is. Select ‘Submit’ to obtain LR based on Full Likelihood Bayes (FLB)",
"label": "PP1",
"ns": "077",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "LOD ≥1.26 or Bayes Factor (LR) ≥18:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "LOD ≥.60 or Bayes Factor (LR) ≥4:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "LOD ≥0.3 or Bayes Factor (LR) ≥2:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584503",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584503",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--G"
},
{
"entContent": {
"_uniqueProp": "077_PVS1_nuclear_PALB2",
"additionalComments": "Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Use PALB2 PVS1 Decision Tree Per PALB2 Exon Map and PALB2 PVS1 Guide \n* PVS1: Predicted splice defect \n* PVS1\\_Strength(RNA): Observed splice defect \n* The default RefSeq transcript for nucleotide (c.) annotation is NM\\_024675.3/ENST00000261584.8. Several naturally occurring alternate splicing isoforms have been described[1](#pmid_30890586). Yet, after careful examination, none of them is considered a candidate rescue transcript (very low contribution to overall expression, not coding proteins predicted functional, or both). In keeping with that, we have considered that all presumed LoF events (PVS1 decision tree specifications) occur in biologically relevant transcript(s).\n* WD40 beta propeller and the Coiled-coil domain (CC) are considered indispensable for PALB2 protein function. \n * PVS1 alterations that are predicted to escape NMD, but that adversely affect the WD40 domain can be granted PVS1 (as opposed to PVS1\\_Strong as the recommended baseline[2](#pmid_30192042). The following evidence supports this strength change: \n * The WD40 domain interacts with many different protein partners that are involved in the double strand break repair pathway[3](#pmid_30638972)\n * Two different C-terminal truncating mutations (c.3549C>A and c.3549C>G) resulting in loss of the last 3 amino acids \\[p.(Tyr1183Ter)\\], were identified in trans with PALB2 stop-gain variants in three unrelated FA (FA-N) patients[4](#pmid_17200671)\n * The PALB2 WD40 toroidal structure is “sealed” in the seventh blade by interaction of the C-terminal strand with the incomplete N-terminal blade. The last four residues of PALB2 (Y1183, H1184, Y1185, and S1186) are directly involved in this interaction (molecular Velcro hydrogen bonding)[00](#pmid_28673926). This is the rationale for the clinical relevance of the last 4 amino acids of the protein.\n * Alterations predicted to lead to in frame losses adversely affecting the WD40 structure/function are found in trans with LoF PALB2 alterations in Fanconi Anemia patients[4](#pmid_17200671)\n * Exon 10 donor: c.3113+5G>C (biallelic with c.395delT)\n * Exon 12 donor: c.3350+4A>G (biallelic with c.2393\\_2394insCT)\n * LoF alterations are rare in GnomAD in all exons\n * GnomAD v2.1 accessed 5/30/2019\n * Total Variants (includes splice acceptor/donor-conservative)\n * 1418 variants\n * 336,349 carriers\n * LoF Flag (excludes splice acceptor/donor-conservative)\n * 95 variants (6.7%)\n * 239 carriers (.07%)\n* PVS1 can be applied as per the PVS1 decision tree.\n * PVS1\\_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. Weight can be further modified based on the quality of the RNA study including consideration of concepts such as:\n * Starting material (where patient material is preferable to in vitro minigene)\n * Use of NMD inhibitors where translation does occur such as cell lines[5](#pmid_9628884)[6](#pmid_7499432)\n * Primer design (to make sure it’s comprehensive to capture possible multicassette events)\n * Method of quantification \n * where e.g. capillary electrophoresis is preferable to estimation by gel band density\n * where SNP analysis is most preferred (where analysis of exonic SNPs and their relative presence in aberrant and WT transcripts is informative)\n * Quantification (where complete effects should have increased weight over incomplete effects)\n * Specific guidance on the use of RNA evidence in variant assessment is not a gene-specific consideration for PALB2 at this time, therefore discretion is left to assessors until further guidance is provided for this general concept from the Sequence Variant Interpretation group.",
"label": "PVS1",
"ns": "077",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use PALB2 PVS1 Decision Tree",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PALB2 PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PALB2 PVS1 Decision Tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use PALB2 PVS1 Decision Tree",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584492",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584492",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--F"
},
{
"entContent": {
"_uniqueProp": "077_BS4_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Quantitative co-segregation analysis is mandated for more accurate assessment of causality for PALB2 alterations. It is strongly preferred that biocurators use a quantitative method that accommodates both pathologies of AD PALB2: breast cancer, ovarian cancer and pancreatic cancer. These methods may be conducted by biostatisticians, particularly if they are able to compute LR scores[9](#pmid_29300386) using multiple phenotypes. \n * PP1\\_Strong: LOD ≥1.26 or Bayes Factor (LR) ≥18:1 \n * PP1\\_Moderate: LOD ≥.60 or Bayes Factor (LR) ≥4:1\n * PP1: LOD ≥0.3 or Bayes Factor (LR) ≥2:1\n * BS4\\_Supporting: LOD ≤-.32 or Bayes Factor (LR) ≤.48\n * BS4\\_Moderate: LOD ≤ -.64 or Bayes Factor (LR) ≤.23\n * BS4: LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1\n* A freely available tool, COOL (COsegregation OnLine) from Bing-Jian Feng’s laboratory can be used to calculate LoD scores for co-segregation analysis \n 1\\. Navigate to COOL (COsegregation OnLine)[11](#url_3e13dc73-4062-5d3f-b4aa-67f233ce7248) \n 2\\. Input ‘PALB2’ into the ‘Input a Gene Symbol’ field (the PALB2 defaults are approved by this VCEP) \n 3\\. Upload your Pedigree File (see COOL (COsegregation OnLine) manual[12](#url_02bc6e53-f375-5e2c-acc1-e4b5e6fce8f9) for formatting) \n 4\\. Leave all defaults as is. Select ‘Submit’ to obtain LR based on Full Likelihood Bayes (FLB)",
"label": "BS4",
"ns": "077",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "LOD ≤ -.64 or Bayes Factor (LR) ≤.23",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "LOD ≤-.32 or Bayes Factor (LR) ≤.48",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584512",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584512",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--J"
},
{
"entContent": {
"_uniqueProp": "077_PM4_nuclear_PALB2",
"additionalComments": "●\tDo not use for in-frame deletions/insertions that are not already PVS1-eligible as no information is available to justify the application of this rule. \n●\tIn addition, missense and small in-frame indels are not yet confirmed as a mechanism of disease for PALB2.\n●\tDo not use for stop-loss due to lack of data on stop-loss variants. \n\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only.",
"label": "PM4",
"ns": "077",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": "Gene-specific, General recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584500",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584500",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--D"
},
{
"entContent": {
"_uniqueProp": "077_PM3_nuclear_PALB2",
"additionalComments": "Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Fanconi Anemia (FA) of any subtype is generally considered an exceedingly rare, severe, early-onset disease with variable features. In the case of _BRCA2_, hypomorphic FA patients have been described who are diagnosed at older ages with less severe phenotypes. The criteria set forth in the tables below are designed to accommodate such hypomorphs and are recommended to be applied to all FA-associated genes which may not be as well described due to the extreme infrequency of their identification, and due to ascertainment bias (for severe phenotype) in the literature.\n\nVariant may not exceed general population frequency >0.01%. Consider other gene panel test results as potential explanation for phenotype. \n\nMultiple unrelated cases are additive. \n\n* Ex. one individual homozygous for a variant with Fanconi gets 2.0 points. Another individual affected with Fanconi Anemia has the same variant and another truncating PALB2 variant with phase unknown gets 2.0 points. In total, there are 4.0 points towards PM3.\n\nPhenotype consistent: Chromosomal breakage with 1 clinical feature OR at least 2 of 3 clinical features from separate categories without chromosomal breakage studies\n\n* Ex. Chromosomal breakage testing + microcephaly / triangular face \n* Ex. (Without chromosomal breakage): Myelodysplastic Syndrome and microcephaly / triangular face. Individuals must have features from at least 2 of 3 distinct Cinical Feature categories below. \n* Positive for chromosome breakage test:\n * Increased chromosome breakage and/or radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC)\n* Clinical features indicative of FA, including \n * Physical features (in ~75% of affected persons), include: \n * prenatal and/or postnatal short stature\n * abnormal skin pigmentation (e.g., café au lait macules, hypo- pigmentation)\n * Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)\n * Microcephaly, triangular face\n * Ophthalmic anomalies\n * Genitourinary tract anomalies.\n * See Orphanet [13](#url_e738c852-705f-5eda-9836-d72955882e91) for full list of >100 HPO terms (and their reported frequency).\n * Pathology findings and laboratory findings (non-cancer related) include\n * progressive bone marrow failure (unrelated to cancer treatment)\n * aplastic anemia\n * Myelodysplastic syndrome\n * Inordinate toxicities from chemotherapy or radiation\n * macrocytosis\n * cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)\n * increased fetal hemoglobin (often precedes anemia). \n * Note: FA patients with very early onset cancer (≤5yr) may not present with hematologic disease, which is reported to have median age at onset of 7 years in FA patients in general[14](#pmid_27929686)\n * Cancer diagnosis ≤5yr, particularly\n * Blood cancers (AML)\n * Brain cancers (medulloblastoma, neuroblastoma)\n * Wilms Tumor\n\nSpecifications are adapted from definitions from GeneReviews (last revision June 3, 2021)",
"label": "PM3",
"ns": "077",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation",
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use Fanconi Anemia PM3 tables",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use Fanconi Anemia PM3 tables",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use Fanconi Anemia PM3 tables",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584499",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584499",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--C"
},
{
"entContent": {
"_uniqueProp": "077_BP7_nuclear_PALB2",
"additionalComments": "BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* BP7: Synonymous and deep intronic\n * Can be used for deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor)\n * May also apply BP4 to achieve Likely Benign\n * Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect\n* BP7\\_Variable(RNA): RNA functional studies\n * Lack of aberrant splice defect: Please see PVS1\\_Variable(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays\n * NOTE: BP4 splice predictions may not be used in conjunction with BP7\\_variable(RNA)",
"label": "BP7",
"ns": "077",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": "General recommendation",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "BP7\\_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "* BP7\\_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "* BP7: Synonymous and deep intronic\n* BP7\\_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584519",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584519",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--E"
},
{
"entContent": {
"_uniqueProp": "077_BP4_nuclear_PALB2",
"additionalComments": "●\tProtein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n●\tRNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing \no\tNOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects)\no\tNOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect)\no\tUse caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism. \n",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "● Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants \n\n● RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing \n\no NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n\no NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) \n\no Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",
"label": "BP4",
"ns": "077",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "● Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants \n\n● RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing \n\no NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n\no NOTE: BP4 for splice predictions may not be applied in conjunction with BP7\\_Variable(RNA) (a lack of observed RNA defect) \n\no Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584516",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584516",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--K"
},
{
"entContent": {
"_uniqueProp": "077_BP2_nuclear_PALB2",
"additionalComments": "Do not use: See Fanconi Anemia BS2 table ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "Use ATM PM3/BP2 table.",
"label": "BP2",
"ns": "077",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": "Gene-specific, Disease-specific, Strength, General recommendation",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584514",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584514",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--B"
},
{
"entContent": {
"_uniqueProp": "077_PP2_nuclear_PALB2",
"additionalComments": "Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "077",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584504",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584504",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi--B"
},
{
"entContent": {
"_uniqueProp": "077_PS3_nuclear_PALB2",
"additionalComments": "●\tProtein: Do not use: Lack of known positive controls \n●\tRNA: Do not use: See code PVS1_Variable(RNA)\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).",
"label": "PS3",
"ns": "077",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": "Gene-specific",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584495",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584495",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--_"
},
{
"entContent": {
"_uniqueProp": "077_BP3_nuclear_PALB2",
"additionalComments": "Do not use: small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2. In addition, PALB2 is not considered to have repetitive regions without known function",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "077",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584515",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584515",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpe--C"
},
{
"entContent": {
"_uniqueProp": "077_PP5_nuclear_PALB2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "077",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584507",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584507",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--F"
},
{
"entContent": {
"_uniqueProp": "077_PP3_nuclear_PALB2",
"additionalComments": "Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants\n* RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing\n * NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) \n * NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1\\_Variable(RNA) codes.\n * Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",
"label": "PP3",
"ns": "077",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "* Protein: Do not use.\n* RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584505",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584505",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--H"
},
{
"entContent": {
"_uniqueProp": "077_PM5_nuclear_PALB2",
"additionalComments": "No rescue splicing isoforms have been identified in ATM.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* For protein: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.\n* Apply as PM5\\_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183\\*\n* Apply to splice variants as PM5\\_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Tyr1183 where PVS1\\_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone",
"label": "PM5",
"ns": "077",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183\\*",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584501",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584501",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpG--E"
},
{
"entContent": {
"_uniqueProp": "077_PS2_nuclear_PALB2",
"additionalComments": "●\tDo not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase\n●\tAutosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified.\n●\tAutosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies.\n",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS2",
"ns": "077",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584494",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584494",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxp6--K"
},
{
"entContent": {
"_uniqueProp": "077_PS1_nuclear_PALB2",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"PALB2"
],
"geneType": "nuclear",
"instructionsToUse": "* **Protein**: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2\n* **Splicing:** See PALB2 PS1 Table (PMID: **37352859)**",
"label": "PS1",
"ns": "077",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use PALB2 PS1 Splicing table",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1566584493",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1566584493",
"modified": "2023-11-28T19:22:51.721Z",
"modifier": "meganholdren",
"rev": "_h6SHxpi---"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015278",
"lbl": "familial pancreatic carcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1385362916"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/419700"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535837"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/715414009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2931038"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C43298"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_1333"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/260350"
}
],
"definition": {
"val": "Familial pancreatic carcinoma is defined by the presence of pancreatic cancer (PC) in two or more first-degree relatives.",
"xrefs": [
"Orphanet:1333"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "familial pancreatic cancer",
"xrefs": [
"NCIT:C43298",
"Orphanet:1333"
]
},
{
"pred": "hasExactSynonym",
"val": "familial pancreatic carcinoma",
"xrefs": [
"NCIT:C43298",
"Orphanet:1333",
"icd11.foundation:1385362916"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary exocrine pancreatic carcinoma",
"xrefs": [
"MONDO:patterns/hereditary"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary pancreatic cancer",
"xrefs": [
"NCIT:C43298"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary pancreatic carcinoma",
"xrefs": [
"NCIT:C43298"
]
},
{
"pred": "hasExactSynonym",
"val": "pancreatic cancer, somatic"
},
{
"pred": "hasExactSynonym",
"val": "pancreatic carcinoma, somatic"
},
{
"pred": "hasRelatedSynonym",
"val": "pancreatic acinar carcinoma"
}
],
"xrefs": [
{
"val": "GARD:4206"
},
{
"val": "MEDGEN:419700"
},
{
"val": "MESH:C535837"
},
{
"val": "NCIT:C43298"
},
{
"val": "OMIM:260350"
},
{
"val": "Orphanet:1333"
},
{
"val": "SCTID:715414009"
},
{
"val": "UMLS:C2931038"
},
{
"val": "icd11.foundation:1385362916"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015278",
"name": "familial pancreatic carcinoma"
},
"entId": "MONDO:0015278",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015278",
"entType": "Disease",
"ldhId": "467895128",
"ldhIri": "https://genboree.org/cspec/Disease/id/467895128",
"modified": "2025-10-07T15:45:31.122Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XXvi---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012565",
"lbl": "Fanconi anemia complementation group N",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012565"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/fanconi_anemia_complementation_group_n"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/372133"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C563657"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1835817"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0111094"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/610832"
}
],
"definition": {
"val": "Any Fanconi anemia in which the cause of the disease is a mutation in the PALB2 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "FANCN",
"xrefs": [
"DOID:0111094",
"MONDO:Lexical",
"OMIM:610832"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi Anemia, complementation group type N",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "Fanconi anaemia caused by mutation in PALB2"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "Fanconi anaemia complementation group type N"
},
{
"pred": "hasExactSynonym",
"val": "Fanconi anemia caused by mutation in PALB2",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi anemia complementation group N",
"xrefs": [
"DOID:0111094"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi anemia complementation group type N",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "PALB2 Fanconi anaemia"
},
{
"pred": "hasExactSynonym",
"val": "PALB2 Fanconi anemia",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Fanconi anemia, complementation group N",
"xrefs": [
"MONDO:Lexical"
]
}
],
"xrefs": [
{
"val": "DOID:0111094"
},
{
"val": "GARD:15500"
},
{
"val": "MEDGEN:372133"
},
{
"val": "MESH:C563657"
},
{
"val": "OMIM:610832"
},
{
"val": "UMLS:C1835817"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012565",
"name": "Fanconi anemia complementation group N"
},
"entId": "MONDO:0012565",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012565",
"entType": "Disease",
"ldhId": "467875876",
"ldhIri": "https://genboree.org/cspec/Disease/id/467875876",
"modified": "2025-10-07T15:44:46.251Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wr5a---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016419",
"lbl": "hereditary breast carcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016419"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hereditary_breast_carcinoma"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/87542"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C562840"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/254843006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0346153"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C4503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_227535"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/114480"
}
],
"comments": [
"Editor note: check w clingen before merge https://github.com/monarch-initiative/mondo/issues/84"
],
"definition": {
"val": "Breast carcinoma that has developed in relatives of patients with history of breast carcinoma.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "breast cancer susceptibility, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, early-onset, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, invasive ductal, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, lobular, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, male, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, protection against, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "familial breast cancer",
"xrefs": [
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial breast carcinoma",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of the breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast cancer",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast carcinoma",
"xrefs": [
"MONDO:patterns/hereditary",
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial"
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial Male"
}
],
"xrefs": [
{
"val": "GARD:17142"
},
{
"val": "ICD10CM:C50.2"
},
{
"val": "ICD10CM:C50.3"
},
{
"val": "ICD10CM:C50.6"
},
{
"val": "MEDGEN:87542"
},
{
"val": "MESH:C562840"
},
{
"val": "NCIT:C4503"
},
{
"val": "OMIM:114480"
},
{
"val": "Orphanet:227535"
},
{
"val": "SCTID:254843006"
},
{
"val": "UMLS:C0346153"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016419",
"name": "hereditary breast carcinoma"
},
"entId": "MONDO:0016419",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016419",
"entType": "Disease",
"ldhId": "467880845",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880845",
"modified": "2025-10-07T15:45:51.651Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XrmW---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056957002842000,
"agr": "HGNC:26144",
"alias_name": [
"Fanconi anemia, complementation group N"
],
"alias_symbol": [
"FLJ21816",
"FANCN"
],
"ccds_id": [
"CCDS32406"
],
"cosmic": "PALB2",
"date_approved_reserved": "2007-01-15",
"date_modified": "2021-05-26",
"ensembl_gene_id": "ENSG00000083093",
"entrez_id": "79728",
"gene_group": [
"WD repeat domain containing",
"FA complementation groups"
],
"gene_group_id": [
362,
548
],
"hgnc_id": "HGNC:26144",
"location": "16p12.2",
"location_sortable": "16p12.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Fanconi Anaemia Mutation Database|http://www2.rockefeller.edu/fanconi",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/FANCN",
"LRG_308|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_308.xml"
],
"mane_select": [
"ENST00000261584.9",
"NM_024675.4"
],
"mgd_id": [
"MGI:3040695"
],
"name": "partner and localizer of BRCA2",
"omim_id": [
"610355"
],
"orphanet": 139189,
"pubmed_id": [
16793542,
17200672
],
"refseq_accession": [
"NM_024675"
],
"rgd_id": [
"RGD:1304759"
],
"status": "Approved",
"symbol": "PALB2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002dlx.2",
"uniprot_ids": [
"Q86YC2"
],
"uuid": "1d3c6d11-bd84-49e6-b37e-a7b515640d0f",
"vega_id": "OTTHUMG00000177097"
}
},
"entId": "PALB2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:26144",
"entType": "Gene",
"ldhId": "467844262",
"ldhIri": "https://genboree.org/cspec/Gene/id/467844262",
"modified": "2021-10-14T11:36:57.241Z",
"modifier": "genbadmin",
"rev": "_h6SHzma--Z"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "077_nuclear_PALB2",
"geneType": "nuclear",
"generalComments": "Version 1.1 updates\n Updated PS1 table to match Splicing SVI recommendations (PMID: 37352859)\nCorrected errors in verbiage/typos for BP4 \nChanged BP4 from not applicable to applicable to make application of BP4 for splicing more visible in CSPEC \nVerbiage update: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing [updated from error in typing that said shows impact]\nVerbiage update: *NOTE: BP4 splice predictions may not be used in conjunction with BP7_variable (RNA) [updated from just BP7 for clarification]. \nAdded BP4 under the combinations for Benign and LB classification [this was omitted in error]",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0016419",
"preferredTitle": "hereditary breast carcinoma"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0015278",
"preferredTitle": "familial pancreatic carcinoma"
},
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0012565",
"preferredTitle": "Fanconi anemia complementation group N"
}
],
"gene": "PALB2",
"preferredTranscript": "NM_024675.3"
}
],
"ns": "077",
"references": [
{
"auths": [
"Lopez-Perolio I",
"Leman R",
"et al."
],
"doiStr": "10.1136/jmedgenet-2018-105834",
"id": "30890586",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 453-460.",
"source": "J Med Genet",
"title": "Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.",
"vol": "56",
"year": "2019"
},
{
"auths": [
"Abou Tayoun AN",
"Pesaran T",
"et al."
],
"doiStr": "10.1002/humu.23626",
"id": "30192042",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1517-1524.",
"source": "Hum Mutat",
"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"Ducy M",
"Sesma-Sanz L",
"et al."
],
"doiStr": "10.1016/j.tibs.2018.10.008",
"id": "30638972",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 226-240.",
"source": "Trends Biochem Sci",
"title": "The Tumor Suppressor PALB2: Inside Out.",
"vol": "44",
"year": "2019"
},
{
"auths": [
"Reid S",
"Schindler D",
"et al."
],
"doiStr": "10.1038/ng1947",
"id": "17200671",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 162-4.",
"source": "Nat Genet",
"title": "Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.",
"vol": "39",
"year": "2007"
},
{
"auths": [
"Thermann R",
"Neu-Yilik G",
"et al."
],
"doiStr": "10.1093/emboj/17.12.3484",
"id": "9628884",
"iss": "(12)",
"namespace": "pmid",
"pages": "p. 3484-94.",
"source": "EMBO J",
"title": "Binary specification of nonsense codons by splicing and cytoplasmic translation.",
"vol": "17",
"year": "1998"
},
{
"auths": [
"Carter MS",
"Doskow J",
"et al."
],
"doiStr": "10.1074/jbc.270.48.28995",
"id": "7499432",
"iss": "(48)",
"namespace": "pmid",
"pages": "p. 28995-9003.",
"source": "J Biol Chem",
"title": "A regulatory mechanism that detects premature nonsense codons in T-cell receptor transcripts in vivo is reversed by protein synthesis inhibitors in vitro.",
"vol": "270",
"year": "1995"
},
{
"id": "5e582422-7218-5d1c-9887-88a8dd6ac60f",
"namespace": "url",
"value": "[https://fengbj-laboratory.org/cool2/server.uu.html](https://fengbj-laboratory.org/cool2/server.uu.html)"
},
{
"id": "5d379a36-2cd8-5961-a6fc-7ce50795ce00",
"namespace": "url",
"value": "[https://fengbj-laboratory.org/cool2/manual.html](https://fengbj-laboratory.org/cool2/manual.html)"
},
{
"auths": [
"Tavtigian SV",
"Greenblatt MS",
"et al."
],
"doiStr": "10.1038/gim.2017.210",
"id": "29300386",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1054-1060.",
"source": "Genet Med",
"title": "Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.",
"vol": "20",
"year": "2018"
},
{
"id": "43417751-122f-5902-830e-7d96b15a14c6",
"namespace": "url",
"value": "[http://cardiodb.org/allelefrequencyapp/](http://cardiodb.org/allelefrequencyapp/:)"
},
{
"id": "3e13dc73-4062-5d3f-b4aa-67f233ce7248",
"namespace": "url",
"value": "https://fengbj-laboratory.org/cool2/server.uu.html"
},
{
"id": "02bc6e53-f375-5e2c-acc1-e4b5e6fce8f9",
"namespace": "url",
"value": "https://fengbj-laboratory.org/cool2/manual.html"
},
{
"id": "e738c852-705f-5eda-9836-d72955882e91",
"namespace": "url",
"value": "https://www.orpha.net/consor/cgi-bin/Disease_HPOTerms_Simple.php?lng=EN"
},
{
"auths": [
"Ebens CL",
"MacMillan ML",
"et al."
],
"doiStr": "10.1080/17474086.2016.1268048",
"id": "27929686",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 81-97.",
"source": "Expert Rev Hematol",
"title": "Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.",
"vol": "10",
"year": "2017"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4",
"BP7_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS4",
"PM3_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PM3",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP1",
"BP4",
"BP7"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule22"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP1",
"BP4",
"BP7"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule22"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1526222369",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1526222369",
"modified": "2023-11-28T19:22:51.647Z",
"modifier": "meganholdren",
"rev": "_h6SHyTW--A"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "HBOP",
"approval": {
"step1": {
"approvalDate": "2018-11-28T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-10-31T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-01-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-01-25T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hereditary Breast, Ovarian and Pancreatic Cancer",
"shortBaseName": "HBOP",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer VCEP",
"title": "Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50039",
"entIri": "http://clinicalgenome.org/affiliation/50039",
"entType": "Organization",
"ldhId": "639508880",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508880",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--T"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1526222356",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1526222356",
"modified": "2023-11-28T19:22:51.591Z",
"modifier": "meganholdren",
"rev": "_h6SHykW---"
},
{
"entContent": {
"approvedOn": "2024-02-29T04:26:34.603Z",
"description": "",
"namespace": "GN078",
"releaseNotes": "Please see clarifications made to PM2, BA1 and BS1. We updated language to gnomAD v4, removed language around using the “non-cancer” set (which did not contain TCGA germline samples) as this set is no longer used in v4. We changed PM2\\_Supporting from complete absence in gnomAD to PM2\\_Supporting ≤ 1.56E-6 GroupMax FAF. This is one order of magnitude less than the BS1 cut-off and strictly limits the presence of variants in gnomAD v4 but does not require complete absence.",
"releasedUnderRevision": true,
"shortTitle": "VHL Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:36:26.972Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-07-12T12:47:31.707Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-23T14:19:44.628Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Approved For Release",
"timeStamp": "2024-01-09T14:19:44.628Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-01-29T17:07:02.255Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2024-02-29T04:26:34.603Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2024-07-12T12:46:39.238Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"078"
],
"title": "ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN078",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP3_nuclear_VHL",
"additionalComments": "Not applicable at this time.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "078",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943306",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943306",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpi--L"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP1_nuclear_VHL",
"additionalComments": "This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "078",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943304",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943304",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpi--I"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP4_nuclear_VHL",
"additionalComments": "Combine with PS4 to avoid double counting probands. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP4",
"ns": "078",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943297",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943297",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC--A"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Meioses can be counted additively across multiple families. This code may only be applied when the phenotype is highly consistent with VHL (Danish Criteria in a family with history of disease).",
"label": "PP1",
"ns": "078",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "\\>7 meioses across >=2 families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "5 – 6 meioses across ≥1 family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "3 – 4 meioses across ≥1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943294",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943294",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpy--G"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS3_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS3",
"ns": "078",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Acceptable assays that display functional effect in VHL are the following: \n\n• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or \n\n• VBC complex stability is affected and/or\n\n• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding [1](#pmid_9651579) , [2](#pmid_11331613) , [3](#pmid_11358843) , [17](#pmid_14706840)\n\nMultiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B. VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3\\_Supporting and 11 for PS3\\_Moderate [10](#pmid_31892348). We propose to _follow the workflow outlined in Brnich et al._ Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. \n\n**SPLICING:** **PS3:** RNA transcripts carrying splicing mutation display splicing defects in patient cells. **PS3\\_Moderate**: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays. **Functional Assay Documentation** : [https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing](https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943286",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943286",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxq---L"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP6_nuclear_VHL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP6",
"ns": "078",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943309",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943309",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC--D"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BS1",
"ns": "078",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use BS1 cut off of >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943300",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943300",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC--B"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP5_nuclear_VHL",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP5",
"ns": "078",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943298",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943298",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--E"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP7_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "078",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943310",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943310",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqK--_"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "The Splice AI score alone can be applied if VarSeak is unable to accept the variant type.",
"label": "BP4",
"ns": "078",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. \n\nBP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943307",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943307",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--G"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BS4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "For BS4, affected members of the pedigree should fulfill the Danish Criteria for VHL. BS4 should not be used if the affected members are only affected with pheochromocytoma (e.g. VHL 2c) and/or Renal Cell Carcinoma. Family members should also be fully characterized for VHL manifestations to be considered unaffected, and be at least 65 years old (age at which full penetrance should be reached).\n\nFor example: two siblings who both have VHL as per the Danish criteria, one has a _VHL_ variant, and the other sibling does not, BS4 could be used. \n\nConversely, two siblings both fully characterized, one sibling has VHL manifestations, the other sibling is >65 yo and does not have VHL manifestations. If both siblings carry the _VHL_ variant, BS4 could be used.\n\nIf the above are fulfilled, BS4 strong could be used if lack of segregation of the variant is seen in affected members of two or more families and BS4\\_supporting be used if one family is observed.\n\nIf a parent fulfills the Danish criteria for VHL disease, but the child is phenotyped and has no manifestations, BS4 cannot be used as the child could develop VHL manifestations at a later age.",
"label": "BS4",
"ns": "078",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation is seen in affected members of ≥2 families",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation is seen in 1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943303",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943303",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC--C"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BS3_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS3",
"ns": "078",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "• HIF 1/2a assay replicates WT function and/or\n\n• VBC complex stability is not affected and/or \n\n• ECM formation/fibronectin binding is unaffected \n\nThis rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943302",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943302",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpy--H"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BS2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "078",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "VHL is not highly penetrant _at an early age._ BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**with full phenotyping and screening**_ for the absence of VHL-related cancers.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "VHL is not highly penetrant _at an early age._ BS2\\_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, _**lacking full phenotyping and screening**_, with no noted VHL-related cancers",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943301",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943301",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpi--H"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BA1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "BA1",
"ns": "078",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943299",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943299",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--F"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP2_nuclear_VHL",
"additionalComments": "Do not use. While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "**Do not use.** While there are known pathogenic missense in VHL, there is also evidence of benign or common missense in VHL. gnomAD shows VHL is not intolerant to missense (Z score = -0.39). Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes.",
"label": "PP2",
"ns": "078",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943295",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943295",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC--_"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Follow all [SVI general guidance](https://clinicalgenome.org/working-groups/sequence-variant-interpretation/) on applying population filters.",
"label": "PM2",
"ns": "078",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PM2\\_Supporting can be applied for variants either absent from gnomAD or with \\<= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2\\_Supporting may also be applied.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943289",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943289",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqK---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP5_nuclear_VHL",
"additionalComments": "Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "078",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a _VHL_ variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the _VHL_ variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a _VHL_ variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943308",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943308",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--H"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_BP2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "BP2 should not be used in the presence of any clinical or molecular findings of congenital polycythemia",
"label": "BP2",
"ns": "078",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)\n\nii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia\n\niii) -OR observed _in cis_ or with unknown phase with three or more different pathogenic _VHL_ variants",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "\\-variant is observed _in cis_ (or phase is unknown) w/ a pathogenic _VHL_ variant",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943305",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943305",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpi--J"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM5_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PM5",
"ns": "078",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 [16](#pmid_4843792) ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943292",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943292",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--C"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "078",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL [15](#pmid_20560986) cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease). The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). \n\nPM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943291",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943291",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpi--G"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "_**See germline and somatic hotspot residue table.**_ PM1 can be used for (1) known germline mutational hotspots, and for (2) currently 11 somatic hotspots (cancerhotspots.org) where there is not already a germline mutational hotspot (see Walsh et al 2018 [11](#pmid_30311369) and cancer hotspots.org(v2) [12](#pmid_29247016) ): Following PM1 somatic hotspot recommendations through the ClinGen Germline/Somatic Subcommittee where: AA with >= 10 somatic occurrences in the same AA can receive PM1, while AA with \\<10 can receive PM1\\_Supporting. It can also be used for (3) location in a key functional domain if a residue is not a germline or somatic hotspot.",
"label": "PM1",
"ns": "078",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Putative missense variants seen in somatic databases, having \\<10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943288",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943288",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--A"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS4_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "**See phenotype and points tables.** When the phenotype meets Danish Criteria (panel is not required, unless only RCC+Pheo. If a case with RCC+Pheo does not have a panel, they are scored as \"Nonspecific\" (0.25 points)), count 1 point per proband. When the phenotype is consistent with VHL but is not highly specific (such as RCC+Pheo) count 0.5 and when not specific and no panel, count as 0.25. Unrelated probands are to be used, and may be aggregated across all three categories (highly specific Danish Criteria, Consistent and Nonspecific). If there is a pedigree with a choice of probands with VHL disease, choose the proband that most closely matches Danish Criteria. When the phenotype is not available (e.g. from a published article on a VHL cohort that does not detail the phenotype), count 0.25 points per proband. For example, for variant A, 2 probands meet Danish Criteria, 2 probands display Pheochromocytoma only and 4 probands were defined as VHL probands in a published manuscript but lack any further specific criteria or phenotypic details. This would be calculated as (2, 1 pt each per Danish Criteria proband) + (1, 0.5 pt each per Consistent proband) + (1, 0.25 pt each per Nonspecific proband) = 4. PS4 would be downgraded to moderate (PS4\\_Moderate).",
"label": "PS4",
"ns": "078",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.**",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943287",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943287",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--_"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PVS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PVS1",
"ns": "078",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**LINK TO PVS1 DECISION TREE DOCUMENT:** [**https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing**](https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing)\n\n**Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)**\n\n**Note1: Exon presence in biologically relevant transcripts:** In some transcripts exon 2 of _VHL_ is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in _VHL_. Exon 3 contains the elongin binding function. _**All exons should be considered as \"present in biologically relevant transcripts\" in the PVS1 decision tree.**_\n\n**Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL** because of the small size.\n\n**Nonsense Mediated Decay** [5](#pmid_22825683) [4](#pmid_20145706) **NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)**.\\*\\*\n\n**Critical Domains:**\n\n1st Beta (β) domain (63-154), especially Nuclear Export (114-155)\n\nAlpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172)\n\nSecond Beta domain (193-204) \n\n_Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1\\_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4)._\n\n**SPLICE: If any canonical exon is skipped, the variant receives PVS1.** If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1\\_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1\\_Strong, and if it is outside the critical domain (AA 205-213) or in an NMD prediction (AA 55-62), it receives PVS1\\_Moderate. Note: There is a cryptic exon (E1) in intron 1 [7](#pmid_31996412) [6](#pmid_29891534), and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. \n\n**EXON DELETION:** SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in _VHL_ and each has an important functional domain. Any exon deletion of _VHL_ receives PVS1. \n\n**EXON DUPLICATION:** Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar. (ID:417571, ID:584137). These have no literature cited. \n\n**INITIATION CODON:** VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent [9](#pmid_26224408) [8](#pmid_27578599), and those heterozygous for M54I did not present VHL phenotype [9](#pmid_26224408).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943283",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943283",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqG--D"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PP3_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "The Splice AI score alone can be applied if VarSeak is unable to accept the variant type. Note: for canonical splice variants do not use PP3 if PVS1 is applied.",
"label": "PP3",
"ns": "078",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For missense variants, use REVEL score >=0.664. \n\nFor splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943296",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943296",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--D"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM6_nuclear_VHL",
"additionalComments": "Combined with PS2. Use PS2 instead of PM6.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "See PS2 evidence code for scoring and phenotypes.",
"label": "PM6",
"ns": "078",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See PS2 evidence code for scoring and phenotypes. Assumed _de novo_ receives half the points as compared to maternity and paternity confirmed _de novo_. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6\\_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6\\_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943293",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943293",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqC---"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PM3_nuclear_VHL",
"additionalComments": "Autosomal dominant.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "078",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943290",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943290",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpK--B"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS2_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": "Use the SVI-recommended scoring system ( 0.5 supporting, 1 moderate, 2 strong, 4 very strong) with disease-specific phenotype detailed as follows: Danish Criteria (see recently updated Danish Criteria [18](#pmid_35709961) ), Consistent Phenotype (1 phenotype of VHL disease without family history or strong indication of VHL phenotype) or Nonspecific Phenotype (specific information on tumor types is not provided). Negative panel testing is required as follows: For Renal Cell Carcinoma, tumor histopathologies should be clear cell and a negative panel should include at least SDHB/C/D and for Pheochromocytoma only negative panels should include at least SDHB/C/D and RET. If paper states Danish or International Criteria but does not provide case-specific details, count these cases as \"Phenotype consistent.\" If there is no family history of VHL disease, Renal Cell Carcinoma and Pheochromocytoma only will count as \"Phenotype consistent\" (with negative panel testing).",
"label": "PS2",
"ns": "078",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 _de novo_ points).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 _de novo_ points)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Phenotype consistent but not highly specific (≥0.5 but less than 1 _de novo_ points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943285",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943285",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxpy--E"
},
{
"created": "2024-02-29T04:26:35.312Z",
"creator": "dritter@bcm.edu",
"entContent": {
"_uniqueProp": "078_PS1_nuclear_VHL",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"VHL"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "078",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1743943284",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1743943284",
"modified": "2024-02-29T04:26:35.312Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHxqG--E"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056967089094700,
"agr": "HGNC:12687",
"alias_symbol": [
"VHL1"
],
"ccds_id": [
"CCDS2598",
"CCDS2597"
],
"cosmic": "VHL",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2016-03-02",
"ena": [
"L15409"
],
"ensembl_gene_id": "ENSG00000134086",
"entrez_id": "7428",
"hgnc_id": "HGNC:12687",
"location": "3p25.3",
"location_sortable": "03p25.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"UMD Locus Specific Databases|http://www.umd.be/",
"LRG_322|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_322.xml"
],
"mane_select": [
"ENST00000256474.3",
"NM_000551.4"
],
"mgd_id": [
"MGI:103223"
],
"name": "von Hippel-Lindau tumor suppressor",
"omim_id": [
"608537"
],
"orphanet": 120467,
"prev_name": [
"von Hippel-Lindau syndrome",
"von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase"
],
"pubmed_id": [
9671762
],
"refseq_accession": [
"NM_000551"
],
"rgd_id": [
"RGD:3960"
],
"status": "Approved",
"symbol": "VHL",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003bvc.4",
"uniprot_ids": [
"P40337"
],
"uuid": "095b54d6-0de0-4035-bc4f-1458f4cc32c2",
"vega_id": "OTTHUMG00000128668"
}
},
"entId": "VHL",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12687",
"entType": "Gene",
"ldhId": "467863504",
"ldhIri": "https://genboree.org/cspec/Gene/id/467863504",
"modified": "2021-10-14T11:37:15.094Z",
"modifier": "genbadmin",
"rev": "_h6SH0Ou--J"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "078_nuclear_VHL",
"geneType": "nuclear",
"genes": [
{
"diseases": [],
"gene": "VHL"
}
],
"ns": "078",
"references": [
{
"auths": [
"Ohh M",
"Yauch RL",
"et al."
],
"doiStr": "10.1016/s1097-2765(00)80096-9",
"id": "9651579",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 959-68.",
"source": "Mol Cell",
"title": "The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.",
"vol": "1",
"year": "1998"
},
{
"auths": [
"Clifford SC",
"Cockman ME",
"et al."
],
"doiStr": "10.1093/hmg/10.10.1029",
"id": "11331613",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 1029-38.",
"source": "Hum Mol Genet",
"title": "Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.",
"vol": "10",
"year": "2001"
},
{
"auths": [
"Kamada M",
"Suzuki K",
"et al."
],
"doiStr": "",
"id": "11358843",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 4184-9.",
"source": "Cancer Res",
"title": "von Hippel-Lindau protein promotes the assembly of actin and vinculin and inhibits cell motility.",
"vol": "61",
"year": "2001"
},
{
"auths": [
"Micale L",
"Muscarella LA",
"et al."
],
"doiStr": "10.1155/2009/860761",
"id": "20145706",
"iss": "",
"namespace": "pmid",
"pages": "p. 860761.",
"source": "J Biomed Biotechnol",
"title": "VHL frameshift mutation as target of nonsense-mediated mRNA decay in Drosophila melanogaster and human HEK293 cell line.",
"vol": "2009",
"year": "2009"
},
{
"auths": [
"Taylor C",
"Craven RA",
"et al."
],
"doiStr": "10.3892/ijo.2012.1561",
"id": "22825683",
"iss": "(4)",
"namespace": "pmid",
"pages": "p. 1229-40.",
"source": "Int J Oncol",
"title": "Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma.",
"vol": "41",
"year": "2012"
},
{
"auths": [
"Lenglet M",
"Robriquet F",
"et al."
],
"doiStr": "10.1182/blood-2018-03-838235",
"id": "29891534",
"iss": "(5)",
"namespace": "pmid",
"pages": "p. 469-483.",
"source": "Blood",
"title": "Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.",
"vol": "132",
"year": "2018"
},
{
"auths": [
"Buffet A",
"Calsina B",
"et al."
],
"doiStr": "10.1136/jmedgenet-2019-106519",
"id": "31996412",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 752-759.",
"source": "J Med Genet",
"title": "Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma.",
"vol": "57",
"year": "2020"
},
{
"auths": [
"Caravita S",
"Deboeck G",
"et al."
],
"doiStr": "10.1016/j.healun.2016.07.002",
"id": "27578599",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1138-9.",
"source": "J Heart Lung Transplant",
"title": "Pulmonary arterial hypertension associated with a von Hippel-Lindau gene mutation.",
"vol": "35",
"year": "2016"
},
{
"auths": [
"Bartels M",
"van der Zalm MM",
"et al."
],
"doiStr": "10.1002/humu.22846",
"id": "26224408",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1039-42.",
"source": "Hum Mutat",
"title": "Novel Homozygous Mutation of the Internal Translation Initiation Start Site of VHL is Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms.",
"vol": "36",
"year": "2015"
},
{
"auths": [
"Brnich SE",
"Abou Tayoun AN",
"et al."
],
"doiStr": "10.1186/s13073-019-0690-2",
"id": "31892348",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 3.",
"source": "Genome Med",
"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
},
{
"auths": [
"Walsh MF",
"Ritter DI",
"et al."
],
"doiStr": "10.1002/humu.23640",
"id": "30311369",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1542-1552.",
"source": "Hum Mutat",
"title": "Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"Chang MT",
"Bhattarai TS",
"et al."
],
"doiStr": "10.1158/2159-8290.CD-17-0321",
"id": "29247016",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 174-183.",
"source": "Cancer Discov",
"title": "Accelerating Discovery of Functional Mutant Alleles in Cancer.",
"vol": "8",
"year": "2018"
},
{
"auths": [
"Hwang S",
"Ku CR",
"et al."
],
"doiStr": "10.1038/jhg.2014.61",
"id": "25078357",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 488-93.",
"source": "J Hum Genet",
"title": "Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.",
"vol": "59",
"year": "2014"
},
{
"auths": [
"Hong B",
"Ma K",
"et al."
],
"doiStr": "10.3389/fgene.2019.00867",
"id": "31620170",
"iss": "",
"namespace": "pmid",
"pages": "p. 867.",
"source": "Front Genet",
"title": "Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease.",
"vol": "10",
"year": "2019"
},
{
"auths": [
"Sorrell AD",
"Lee S",
"et al."
],
"doiStr": "10.1111/j.1399-0004.2010.01464.x",
"id": "20560986",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 539-45.",
"source": "Clin Genet",
"title": "Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.",
"vol": "79",
"year": "2011"
},
{
"auths": [
"Grantham R"
],
"doiStr": "10.1126/science.185.4154.862",
"id": "4843792",
"iss": "(4154)",
"namespace": "pmid",
"pages": "p. 862-4.",
"source": "Science",
"title": "Amino acid difference formula to help explain protein evolution.",
"vol": "185",
"year": "1974"
},
{
"auths": [
"Bluyssen HA",
"Lolkema MP",
"et al."
],
"doiStr": "10.1016/s0014-5793(03)01392-9",
"id": "14706840",
"iss": "(1-3)",
"namespace": "pmid",
"pages": "p. 137-42.",
"source": "FEBS Lett",
"title": "Fibronectin is a hypoxia-independent target of the tumor suppressor VHL.",
"vol": "556",
"year": "2004"
},
{
"auths": [
"Louise M Binderup M",
"Smerdel M",
"et al."
],
"doiStr": "10.1016/j.ejmg.2022.104538",
"id": "35709961",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 104538.",
"source": "Eur J Med Genet",
"title": "von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.",
"vol": "65",
"year": "2022"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule10, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule10, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule10"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4",
"BP2_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4",
"BP2_Strong"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BS4_Supporting",
"BP2",
"BP3",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BS4_Supporting",
"BP2",
"BP3",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1527855768",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1527855768",
"modified": "2024-02-29T04:26:35.206Z",
"modifier": "dritter@bcm.edu",
"rev": "_h6SHyTW--K"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "VHL",
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-04-22T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2024-01-29T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2024-02-26T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "VHL",
"shortBaseName": "VHL",
"shortTitle": "VHL VCEP",
"title": "VHL Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50036",
"entIri": "http://clinicalgenome.org/affiliation/50036",
"entType": "Organization",
"ldhId": "639508878",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508878",
"modified": "2024-02-27T18:56:14.518Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--j"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1527855755",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527855755",
"modified": "2024-07-12T12:47:31.963Z",
"modifier": "devScorer",
"rev": "_iIZ6-mm---"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome",
"namespace": "GN079",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:45:18.591Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:02:49.573Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:24.643Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:38:19.850Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"079"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN079",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009276",
"lbl": "Bernard-Soulier syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009276"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/bernard_soulier_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10057473"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/507309898"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2212"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D001606"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/234478007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0005129"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_2217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84595"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_274"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/231200"
}
],
"definition": {
"val": "Bernard Soulier syndrome (BSS) is an inherited platelet disorder characterized by mild to severe bleeding tendency, macrothrombocytopenia and absent ristocetin-induced platelet agglutination.",
"xrefs": [
"Orphanet:274"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Bernard - Soulier thrombopathy",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard Soulier syndrome",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome",
"xrefs": [
"DOID:2217",
"MONDO:Lexical",
"NCIT:C84595",
"OMIM:231200",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome, type A1 (recessive)"
},
{
"pred": "hasExactSynonym",
"val": "Hemorrhagiparous thrombocytic dystrophy",
"xrefs": [
"Orphanet:274"
]
},
{
"pred": "hasExactSynonym",
"val": "giant platelet disorder, isolated"
},
{
"pred": "hasExactSynonym",
"val": "giant platelet syndrome",
"xrefs": [
"DOID:2217",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "hemorrhagic dystrophic thrombocytopenia",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "thrombopathy, Bernard-Soulier",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BSS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type A1"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type B"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type C"
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein 1b, deficiency of",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein Ib deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand Factor receptor deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "bleeding disorder, Platelet-type, 1"
},
{
"pred": "hasRelatedSynonym",
"val": "deficiency of platelet glycoprotein 1b",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "giant platelet disease",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "glycoprotein Ib, Platelet, deficiency of"
},
{
"pred": "hasRelatedSynonym",
"val": "macrothrombocytopenia, familial Bernard-Soulier type",
"xrefs": [
"GARD:0002470"
]
}
],
"xrefs": [
{
"val": "DOID:2217"
},
{
"val": "GARD:2470"
},
{
"val": "MEDGEN:2212"
},
{
"val": "MESH:D001606"
},
{
"val": "MedDRA:10057473"
},
{
"val": "NANDO:2200656"
},
{
"val": "NCIT:C84595"
},
{
"val": "NORD:851"
},
{
"val": "OMIM:231200"
},
{
"val": "Orphanet:274"
},
{
"val": "SCTID:234478007"
},
{
"val": "UMLS:C0005129"
},
{
"val": "icd11.foundation:507309898"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009276",
"name": "Bernard-Soulier syndrome"
},
"entId": "MONDO:0009276",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009276",
"entType": "Disease",
"ldhId": "467874358",
"ldhIri": "https://genboree.org/cspec/Disease/id/467874358",
"modified": "2025-10-07T15:43:53.305Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V4O2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948593262600,
"agr": "HGNC:4439",
"alias_name": [
"platelet glycoprotein Ib alpha chain"
],
"alias_symbol": [
"CD42b",
"GPIbalpha"
],
"ccds_id": [
"CCDS54068"
],
"cd": "CD42b",
"date_approved_reserved": "1990-09-10",
"date_modified": "2021-04-13",
"date_name_changed": "2018-04-23",
"ensembl_gene_id": "ENSG00000185245",
"entrez_id": "2811",
"gene_group": [
"CD molecules"
],
"gene_group_id": [
471
],
"hgnc_id": "HGNC:4439",
"location": "17p13.2",
"location_sortable": "17p13.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_480|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_480.xml"
],
"mane_select": [
"ENST00000329125.6",
"NM_000173.7"
],
"mgd_id": [
"MGI:1333744"
],
"name": "glycoprotein Ib platelet subunit alpha",
"omim_id": [
"606672"
],
"orphanet": 122237,
"prev_name": [
"glycoprotein Ib (platelet), alpha polypeptide"
],
"prev_symbol": [
"GP1B"
],
"pubmed_id": [
3353370
],
"refseq_accession": [
"NM_000173"
],
"rgd_id": [
"RGD:1310239"
],
"status": "Approved",
"symbol": "GP1BA",
"ucsc_id": "uc021tnz.1",
"uniprot_ids": [
"P07359"
],
"uuid": "c69b6e86-b53f-4dc3-a139-f2870cd0ab20",
"vega_id": "OTTHUMG00000177946"
}
},
"entId": "GP1BA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4439",
"entType": "Gene",
"ldhId": "467828070",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828070",
"modified": "2021-10-14T11:36:40.599Z",
"modifier": "genbadmin",
"rev": "_h6SHyrW--a"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "079_nuclear_GP1BA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0009276",
"preferredTitle": "Bernard-Soulier syndrome"
}
],
"gene": "GP1BA",
"preferredTranscript": "NM_000173.7"
}
],
"ns": "079",
"references": []
},
"entType": "RuleSet",
"ldhId": "1527857191",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1527857191",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--K"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1527857178",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527857178",
"modified": "2023-05-10T20:38:20.101Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyj6--L"
},
{
"entContent": {
"approvedOn": "2023-10-05T13:25:41.651Z",
"description": "Rule specifications for hemophilia B.",
"namespace": "GN080",
"releaseNotes": "Edits post SVI review",
"shortTitle": "Coagulation Factor Deficiency Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-28T19:49:44.254Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-06-13T15:31:23.630Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-02-07T15:39:45.376Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-03-08T23:19:54.383Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-09-01T16:22:13.358Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-05T13:25:41.651Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"080"
],
"title": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN080",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP6_nuclear_F9",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "080",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363716",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363716",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpm--_"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia B phenotype requirements:** \n\\-Abnormal factor IX activity levels in the severe, moderate or mild range (\\< 40% factor IX activity level) are sufficient to confer a diagnosis. \n\\-Variants associated with moderate or severe disease should be absent in gnomAD or other population databases. However, variants associated with mild disease severity can be observed in up to 3 males in population databases, as long as the number of probands would qualify this code to be used at a very strong weight. Variants associated with mild disease severity with 1-2 alleles in population databases must qualify this code to be used at a strong weight.",
"label": "PS4",
"ns": "080",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥8 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-7 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3 probands meet criteria described below",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1 proband meets criteria described below",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363706",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363706",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--A"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP2_nuclear_F9",
"additionalComments": "Not being used at this time. There are reports of males with hemophilia having two suspicious pathogenic variants.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Evidence code is dependent on the strength of data. Take consideration of the quality of sequencing data when applying code.",
"label": "BP2",
"ns": "080",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363700",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363700",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--L"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS1_nuclear_F9",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "080",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363699",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363699",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--I"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP1_nuclear_F9",
"additionalComments": "Not applicable for F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "080",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363696",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363696",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--H"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": ".",
"label": "PM4",
"ns": "080",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code with no specification.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363693",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363693",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--I"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "PM2",
"ns": "080",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant must be absent in males in population databases, such as gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363715",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363715",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--G"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP4_nuclear_F9",
"additionalComments": "Use PS4 to count probands with hemophilia B diagnosis.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "**Hemophilia B phenotype requirements:** \n\\-Abnormal factor IX activity levels in the severe, moderate or mild range (\\< 40% factor IX activity level) are sufficient to confer a diagnosis. \n\\-A proband must have had full gene sequencing and deletion/duplication analysis to apply this code.\n\n\\-A proband used for this code cannot be applied towards the PS4 count.",
"label": "PP4",
"ns": "080",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Proband must meet hemophilia B phenotype criteria AND have full gene sequencing and deletion/duplication analysis.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363713",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363713",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--B"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP5_nuclear_F9",
"additionalComments": "This rule code is not recommended for use at this time. There is no known alternate cause of isolated factor IX deficiency.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).",
"label": "BP5",
"ns": "080",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363708",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363708",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--C"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "See functional study spreadsheet.",
"label": "PS3",
"ns": "080",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Abnormal factor IX activity level (\\<40 IU/dL or 40%) in a cell line and/or mouse model.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Abnormal factor IX activity level (\\<40 IU/dL or 40%) studied in an animal model setting other than mouse (i.e. – bovine factor IX activity levels compared to factor X levels).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent or significantly reduced factor IX antigen level compared to wildtype using conformation-specific reporter assay in cell lines.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363703",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363703",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpi---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS4",
"ns": "080",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F9_ variant is observed in a male with a family history of hemophilia B and has a normal factor IX activity level.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363697",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363697",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--K"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS3",
"ns": "080",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This code can be used for _F9_ gene variants studied in a cell line or mouse model setting that confer a normal factor IX activity AND normal factor IX antigen levels **OR** normal Western Blot.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363694",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363694",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--K"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP5_nuclear_F9",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "080",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363717",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363717",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--W"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM1_nuclear_F9",
"additionalComments": "Not applicable for CDH1.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "The combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM1",
"ns": "080",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This code can be used for variants affecting any of the 3 catalytic residues (H267, D315 or S411) and 2 activation residues (R191-A192 and R226-V227) in the _F9_ gene (PMID: 12554099).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code should be applied when the variant is within exons 3, 4 or 5.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363714",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363714",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpm---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP7_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "This code can also be used for non-canonical intronic variants. The use of BP7 with BP4 is allowed, as appropriate, to classify variants meeting both criteria as likely benign.",
"label": "BP7",
"ns": "080",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Splicing prediction score of less than or equal to 0.01 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363712",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363712",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--F"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP3_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "PP3",
"ns": "080",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363711",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363711",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--E"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BA1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BA1",
"ns": "080",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "MAF cutoff of greater than or equal to 0.0000556 (or 0.00556%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363709",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363709",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--D"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PVS1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Apply the ClinGen Coagulation Factor Deficiency VCEP/SVI decision tree to determine use and strength of the PVS1 rule.",
"label": "PVS1",
"ns": "080",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363707",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363707",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--M"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Base strength of rule code on number of meioses across one or more families.",
"label": "PP1",
"ns": "080",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This code is applicable when there ≥4 meioses across ≥2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code is applicable when there are at least 3 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This code is applicable when there 2 meioses in one family **OR** 1 meiosis between 2 affected siblings.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363705",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363705",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--_"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP4_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BP4",
"ns": "080",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.01.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363704",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363704",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpK---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BP3_nuclear_F9",
"additionalComments": "Not applicable for F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "080",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363702",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363702",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--V"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM5_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "The combined weight of codes PM1 and PM5 applied for a single variant can only equal strong.",
"label": "PM5",
"ns": "080",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ rule specification from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on _F9_ rule specifications Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. A “highly suspicious” VUS is defined as a variant that is 1 supporting code away from reaching a likely pathogenic classification.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363695",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363695",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--J"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "none",
"label": "BS2",
"ns": "080",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code can be used when a _F9_ variant is observed in a male with a normal factor IX activity level (\\<40% IU).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363692",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363692",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--G"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM3_nuclear_F9",
"additionalComments": "Not applicable for the F9 gene.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "080",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363691",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363691",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--U"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PP2_nuclear_F9",
"additionalComments": "Not applicable for F9.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "080",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363710",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363710",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpi--A"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PM6_nuclear_F9",
"additionalComments": "This rule code is combined with PS2. Please combined assumed de novo cases with confirmed de novo cases and apply PS2 at the appropriate weight.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo point system for a highly specific phenotype.",
"label": "PM6",
"ns": "080",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363698",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363698",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpG--L"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_BS1_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "99.99% CI; subpopulation must have a minimum of five variant alleles present. Males and females are included for this code.",
"label": "BS1",
"ns": "080",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "MAF cutoff of greater than or equal to 0.00000556 (or 0.000556%).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363690",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363690",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpS---"
},
{
"created": "2023-10-05T13:25:42.197Z",
"creator": "leekristy",
"entContent": {
"_uniqueProp": "080_PS2_nuclear_F9",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"F9"
],
"geneType": "nuclear",
"instructionsToUse": "Use ClinGen’s de novo modified point system for a highly specific phenotype (see guidance below). Combine all assumed and confirmed de novo cases for this code and use at the appropriate strength based on amount of points for all probands. Probands must meet the PS4 phenotype criteria to apply this code.",
"label": "PS2",
"ns": "080",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1620363701",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1620363701",
"modified": "2023-10-05T13:25:42.197Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--J"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0010604",
"lbl": "hemophilia B",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9097"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0010604"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hemophilia_b"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/8732/hemophilia-b"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10016077"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1901375668"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/945"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002836"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/41788008"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0008533"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/D67"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12259"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C26721"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_98879"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/306900"
}
],
"definition": {
"val": "Hemophilia B is a form of hemophilia characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency.",
"xrefs": [
"Orphanet:98879"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Christmas disease",
"xrefs": [
"NCIT:C26721",
"OMIM:306900",
"Orphanet:98879",
"icd11.foundation:1901375668"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital factor IX deficiency",
"xrefs": [
"DOID:12259",
"Orphanet:98879"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital factor IX disorder",
"xrefs": [
"DOID:12259",
"ICD9CM:286.1"
]
},
{
"pred": "hasExactSynonym",
"val": "deficiency, functional factor IX",
"xrefs": [
"DOID:12259"
]
},
{
"pred": "hasExactSynonym",
"val": "factor IX deficiency",
"xrefs": [
"DOID:12259",
"NCIT:C26721"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia b, X-linked recessive"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia type B"
},
{
"pred": "hasExactSynonym",
"val": "hemophilia B",
"xrefs": [
"DOID:12259",
"MONDO:Lexical",
"NCIT:C26721",
"OMIM:306900",
"Orphanet:98879"
]
},
{
"pred": "hasExactSynonym",
"val": "hemophilia b, X-linked recessive"
},
{
"pred": "hasExactSynonym",
"val": "hemophilia type B",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary Factor IX deficiency",
"xrefs": [
"NCIT:C26721"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary Factor IX deficiency disease",
"xrefs": [
"NCIT:C26721"
]
},
{
"pred": "hasRelatedSynonym",
"val": "F9 deficiency"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "HEMB",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "factor 9 deficiency"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia B Leyden"
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "haemophilia B(M)"
},
{
"pred": "hasRelatedSynonym",
"val": "hem B",
"xrefs": [
"GARD:0008732"
]
},
{
"pred": "hasRelatedSynonym",
"val": "hemophilia B Leyden"
},
{
"pred": "hasRelatedSynonym",
"val": "hemophilia B(M)"
},
{
"pred": "hasRelatedSynonym",
"val": "plasma thromboplastin component deficiency"
}
],
"xrefs": [
{
"val": "DOID:12259"
},
{
"val": "GARD:8732"
},
{
"val": "ICD10CM:D67"
},
{
"val": "ICD9:286.1"
},
{
"val": "MEDGEN:945"
},
{
"val": "MESH:D002836"
},
{
"val": "MedDRA:10016077"
},
{
"val": "NANDO:2200677"
},
{
"val": "NCIT:C26721"
},
{
"val": "NORD:1222"
},
{
"val": "OMIM:306900"
},
{
"val": "Orphanet:98879"
},
{
"val": "SCTID:41788008"
},
{
"val": "UMLS:C0008533"
},
{
"val": "icd11.foundation:1901375668"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0010604",
"name": "hemophilia B"
},
"entId": "MONDO:0010604",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0010604",
"entType": "Disease",
"ldhId": "467893780",
"ldhIri": "https://genboree.org/cspec/Disease/id/467893780",
"modified": "2025-10-07T15:44:15.250Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WNZS---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056947223822300,
"agr": "HGNC:3551",
"alias_name": [
"Factor IX",
"plasma thromboplastic component",
"Christmas disease",
"hemophilia B"
],
"alias_symbol": [
"FIX"
],
"ccds_id": [
"CCDS14666",
"CCDS83495"
],
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2008-08-01",
"ena": [
"M11309"
],
"ensembl_gene_id": "ENSG00000101981",
"entrez_id": "2158",
"enzyme_id": [
"3.4.21.22"
],
"gene_group": [
"Gla domain containing"
],
"gene_group_id": [
1250
],
"hgnc_id": "HGNC:3551",
"iuphar": "objectId:2364",
"location": "Xq27.1",
"location_sortable": "Xq27.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/F9",
"LRG_556|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_556.xml"
],
"mane_select": [
"ENST00000218099.7",
"NM_000133.4"
],
"merops": "S01.214",
"mgd_id": [
"MGI:88384"
],
"name": "coagulation factor IX",
"omim_id": [
"300746"
],
"orphanet": 121683,
"refseq_accession": [
"NM_000133"
],
"rgd_id": [
"RGD:2589"
],
"status": "Approved",
"symbol": "F9",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc004fas.2",
"uniprot_ids": [
"P00740"
],
"uuid": "a57a59e6-feda-4b5f-bddc-b36694d4eb54",
"vega_id": "OTTHUMG00000022536"
}
},
"entId": "F9",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:3551",
"entType": "Gene",
"ldhId": "467825577",
"ldhIri": "https://genboree.org/cspec/Gene/id/467825577",
"modified": "2021-10-14T11:36:38.014Z",
"modifier": "genbadmin",
"rev": "_h6SHypO--N"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "080_nuclear_F9",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "X-linked inheritance",
"preferredMondoId": "MONDO:0010604",
"preferredTitle": "hemophilia B"
}
],
"gene": "F9",
"preferredTranscript": "NM_000133.4"
}
],
"ns": "080",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM1_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS2_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1527859065",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1527859065",
"modified": "2023-10-05T13:25:42.128Z",
"modifier": "leekristy",
"rev": "_h6SHyTO--J"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CoagFactor",
"approval": {
"step1": {
"approvalDate": "2019-05-06T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2020-02-19T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-09-01T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-10-02T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Coagulation Factor Deficiency",
"shortBaseName": "CoagFactor",
"shortTitle": "Coagulation Factor Deficiency VCEP",
"title": "Coagulation Factor Deficiency Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50041",
"entIri": "http://clinicalgenome.org/affiliation/50041",
"entType": "Organization",
"ldhId": "639508881",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508881",
"modified": "2023-10-03T23:07:05.645Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEG--V"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1527859052",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1527859052",
"modified": "2023-10-05T13:25:42.077Z",
"modifier": "leekristy",
"rev": "_h6SHykK--B"
},
{
"entContent": {
"description": "Rule specifications for von Willebrand disease type 2A, 2B and 2M.",
"namespace": "GN081",
"releaseNotes": "",
"shortTitle": "von Willebrand Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T17:46:24.625Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2022-12-13T13:32:24.226Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-09T20:57:53.636Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-06T15:51:24.825Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-29T16:03:23.651Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-15T19:22:14.559Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T22:59:24.376Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"081"
],
"title": "ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN081",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015629",
"lbl": "von Willebrand disease type 2B",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015629"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1383884415"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/224831"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359717002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359721009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1282971"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C131687"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166087"
}
],
"definition": {
"val": "A subtype of type 2 VWD characterized by a bleeding disorder associated with an increase in the affinity of the Willebrand factor (von Willebrand factor; VWF) for platelets. This anomaly results in spontaneous binding of high molecular weight VWF multimers to platelets leading to rapid clearance of both the platelets (increasing the risk of thrombocytopenia) and the high molecular weight VWF multimers from the plasma.",
"xrefs": [
"Orphanet:166087"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease type 2B",
"xrefs": [
"Orphanet:166087",
"icd11.foundation:1383884415"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, type 2B",
"xrefs": [
"NCIT:C131687"
]
}
],
"xrefs": [
{
"val": "GARD:17022"
},
{
"val": "MEDGEN:224831"
},
{
"val": "NCIT:C131687"
},
{
"val": "Orphanet:166087"
},
{
"val": "SCTID:359717002"
},
{
"val": "SCTID:359721009"
},
{
"val": "UMLS:C1282971"
},
{
"val": "icd11.foundation:1383884415"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015629",
"name": "von Willebrand disease type 2B"
},
"entId": "MONDO:0015629",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015629",
"entType": "Disease",
"ldhId": "467885567",
"ldhIri": "https://genboree.org/cspec/Disease/id/467885567",
"modified": "2025-10-07T15:45:38.322Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xene---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0024574",
"lbl": "von Willebrand disease (hereditary or acquired)",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/22686"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D014842"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/128105004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0042974"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/D68.0"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C68677"
}
],
"definition": {
"val": "Hereditary or acquired coagulation disorder characterized by a qualitative or quantitative deficiency of the von Willebrand factor. The latter plays an important role in platelet adhesion. Signs and symptoms include bruises, nose bleeding, gum bleeding following a dental procedure, heavy menstrual bleeding, and gastrointestinal bleeding.",
"xrefs": [
"NCIT:C68677"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "VWD"
},
{
"pred": "hasExactSynonym",
"val": "Von Willebrand Disease",
"xrefs": [
"NCIT:C68677",
"NORD:1831"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disorder",
"xrefs": [
"NCIT:C68677"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand's disease",
"xrefs": [
"ICD10CM:D68.0",
"NCIT:C68677"
]
},
{
"pred": "hasRelatedSynonym",
"val": "von Willebrand disease"
}
],
"xrefs": [
{
"val": "ICD10CM:D68.0"
},
{
"val": "ICD9:286.4"
},
{
"val": "MEDGEN:22686"
},
{
"val": "MESH:D014842"
},
{
"val": "NANDO:2200682"
},
{
"val": "NCIT:C68677"
},
{
"val": "SCTID:128105004"
},
{
"val": "UMLS:C0042974"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0024574",
"name": "von Willebrand disease (hereditary or acquired)"
},
"entId": "MONDO:0024574",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0024574",
"entType": "Disease",
"ldhId": "467875969",
"ldhIri": "https://genboree.org/cspec/Disease/id/467875969",
"modified": "2025-10-07T15:47:37.602Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7ZTLS---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015630",
"lbl": "von Willebrand disease type 2M",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1358085002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/266186"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359725000"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359729006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1282974"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C131688"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166090"
}
],
"comments": [
"Editor note: 2 sctitds refer to same disease"
],
"definition": {
"val": "A subtype of type 2 VWD characterized by a bleeding disorder associated with a decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for platelets and the subendothelium in the absence of any deficiency of high molecular weight VWF multimers.",
"xrefs": [
"Orphanet:166090"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, type 2M",
"xrefs": [
"NCIT:C131688"
]
}
],
"xrefs": [
{
"val": "GARD:17023"
},
{
"val": "MEDGEN:266186"
},
{
"val": "NCIT:C131688"
},
{
"val": "Orphanet:166090"
},
{
"val": "SCTID:359725000"
},
{
"val": "SCTID:359729006"
},
{
"val": "UMLS:C1282974"
},
{
"val": "icd11.foundation:1358085002"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015630",
"name": "von Willebrand disease type 2M"
},
"entId": "MONDO:0015630",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015630",
"entType": "Disease",
"ldhId": "467885578",
"ldhIri": "https://genboree.org/cspec/Disease/id/467885578",
"modified": "2025-10-07T15:45:38.322Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xenu---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0013304",
"lbl": "von Willebrand disease 2",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/von_willebrand_disease_type_2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/224736"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D056728"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/128107007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1264040"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060574"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/613554"
}
],
"definition": {
"val": "Type 2 von Willebrand disease (type 2 VWD) is a form of VWD characterized by a bleeding disorder associated with a qualitative deficiency and functional anomalies of the Willebrand factor (von Willebrand factor; VWF).",
"xrefs": [
"Orphanet:166081"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "VWD type 2",
"xrefs": [
"DOID:0060574"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "VWD2",
"xrefs": [
"DOID:0060574",
"MONDO:Lexical",
"OMIM:613554"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease 2"
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease type 2",
"xrefs": [
"DOID:0060574",
"Orphanet:166081"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease type II",
"xrefs": [
"DOID:0060574"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, types 2A, 2B, 2M, and 2N"
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand's disease type 2",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "von willebrand's disease 2",
"xrefs": [
"DOID:0060574",
"doi:10.1093/jama/9780195176339.003.0016"
]
},
{
"pred": "hasRelatedSynonym",
"val": "VON WILLEBRAND disease, type 2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "VWD, type 2"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand disease, type 2"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand disease, type 2A"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand disease, type 2B"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand disease, type 2M"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand disease, type 2N"
}
],
"xrefs": [
{
"val": "DOID:0060574"
},
{
"val": "GARD:17020"
},
{
"val": "MEDGEN:224736"
},
{
"val": "MESH:D056728"
},
{
"val": "OMIM:613554"
},
{
"val": "Orphanet:166081"
},
{
"val": "SCTID:128107007"
},
{
"val": "UMLS:C1264040"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0013304",
"name": "von Willebrand disease 2"
},
"entId": "MONDO:0013304",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0013304",
"entType": "Disease",
"ldhId": "467884028",
"ldhIri": "https://genboree.org/cspec/Disease/id/467884028",
"modified": "2025-10-07T15:44:59.007Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7W4I----"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015628",
"lbl": "von Willebrand disease type 2A",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1009291548"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/220920"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359714009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1282968"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C131686"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166084"
}
],
"definition": {
"val": "Type 2A von Willebrand disease (type 2A VWD) is a subtype of type 2 VWD characterized by a bleeding disorder associated with a decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for platelets and the subendothelium caused by a deficiency of high molecular weight VWF multimers.",
"xrefs": [
"Orphanet:166084"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, type 2A",
"xrefs": [
"NCIT:C131686"
]
}
],
"xrefs": [
{
"val": "GARD:17021"
},
{
"val": "MEDGEN:220920"
},
{
"val": "NCIT:C131686"
},
{
"val": "Orphanet:166084"
},
{
"val": "SCTID:359714009"
},
{
"val": "UMLS:C1282968"
},
{
"val": "icd11.foundation:1009291548"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015628",
"name": "von Willebrand disease type 2A"
},
"entId": "MONDO:0015628",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015628",
"entType": "Disease",
"ldhId": "467885569",
"ldhIri": "https://genboree.org/cspec/Disease/id/467885569",
"modified": "2025-10-07T15:45:38.322Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XenO---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056967233798100,
"agr": "HGNC:12726",
"ccds_id": [
"CCDS8539"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"ensembl_gene_id": "ENSG00000110799",
"entrez_id": "7450",
"gene_group": [
"Receptor ligands"
],
"gene_group_id": [
542
],
"hgnc_id": "HGNC:12726",
"iuphar": "ligandId:6755",
"location": "12p13.31",
"location_sortable": "12p13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Von Willebrand Factor Database|http://vwf.group.shef.ac.uk/",
"LRG_587|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_587.xml"
],
"mane_select": [
"ENST00000261405.10",
"NM_000552.5"
],
"mgd_id": [
"MGI:98941"
],
"name": "von Willebrand factor",
"omim_id": [
"613160"
],
"orphanet": 120487,
"prev_symbol": [
"F8VWF"
],
"pubmed_id": [
2251280
],
"refseq_accession": [
"NM_000552"
],
"rgd_id": [
"RGD:621759"
],
"status": "Approved",
"symbol": "VWF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001qnn.2",
"uniprot_ids": [
"P04275"
],
"uuid": "d06e9de2-4d03-4710-8a4f-542fcb6e4074",
"vega_id": "OTTHUMG00000168265"
}
},
"entId": "VWF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12726",
"entType": "Gene",
"ldhId": "467863817",
"ldhIri": "https://genboree.org/cspec/Gene/id/467863817",
"modified": "2021-10-14T11:37:15.362Z",
"modifier": "genbadmin",
"rev": "_h6SH0P---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "081_nuclear_VWF",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0015628",
"preferredTitle": "von Willebrand disease type 2A"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0015629",
"preferredTitle": "von Willebrand disease type 2B"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0015630",
"preferredTitle": "von Willebrand disease type 2M"
},
{
"preferredModeOfInheritance": "Undetermined mode of inheritance",
"preferredMondoId": "MONDO:0013304",
"preferredTitle": "von Willebrand disease 2"
},
{
"adjective": "None",
"preferredModeOfInheritance": "Other",
"preferredMondoId": "MONDO:0024574",
"preferredTitle": "von Willebrand disease (hereditary or acquired)"
}
],
"gene": "VWF",
"preferredTranscript": "NM_000552.5"
}
],
"ns": "081",
"references": []
},
"entType": "RuleSet",
"ldhId": "1528062428",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528062428",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyS6--M"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "VWD",
"approval": {
"step1": {
"approvalDate": "2019-12-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-01-06T15:51:24.825Z",
"approved": true
},
"step3": {
"approvalDate": "2024-06-07T16:33:27.420Z",
"approved": true
},
"step4": {
"approvalDate": "2024-06-24T16:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "von Willebrand Disease ",
"shortBaseName": "VWD",
"shortTitle": "von Willebrand Disease VCEP",
"title": "von Willebrand Disease Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50051",
"entIri": "http://clinicalgenome.org/affiliation/50051",
"entType": "Organization",
"ldhId": "639508886",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508886",
"modified": "2024-07-08T12:29:32.500Z",
"modifier": "cspecAdministrator",
"rev": "_iHHQEcW---"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528062415",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528062415",
"modified": "2024-02-29T16:03:23.854Z",
"modifier": "leekristy",
"rev": "_h6SHykG--H"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome associated with the GP1BB gene.",
"namespace": "GN082",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:24:29.972Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:03:09.005Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:54.589Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:39:45.728Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"082"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BB Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN082",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009276",
"lbl": "Bernard-Soulier syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009276"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/bernard_soulier_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10057473"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/507309898"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2212"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D001606"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/234478007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0005129"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_2217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84595"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_274"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/231200"
}
],
"definition": {
"val": "Bernard Soulier syndrome (BSS) is an inherited platelet disorder characterized by mild to severe bleeding tendency, macrothrombocytopenia and absent ristocetin-induced platelet agglutination.",
"xrefs": [
"Orphanet:274"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Bernard - Soulier thrombopathy",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard Soulier syndrome",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome",
"xrefs": [
"DOID:2217",
"MONDO:Lexical",
"NCIT:C84595",
"OMIM:231200",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome, type A1 (recessive)"
},
{
"pred": "hasExactSynonym",
"val": "Hemorrhagiparous thrombocytic dystrophy",
"xrefs": [
"Orphanet:274"
]
},
{
"pred": "hasExactSynonym",
"val": "giant platelet disorder, isolated"
},
{
"pred": "hasExactSynonym",
"val": "giant platelet syndrome",
"xrefs": [
"DOID:2217",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "hemorrhagic dystrophic thrombocytopenia",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "thrombopathy, Bernard-Soulier",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BSS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type A1"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type B"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type C"
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein 1b, deficiency of",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein Ib deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand Factor receptor deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "bleeding disorder, Platelet-type, 1"
},
{
"pred": "hasRelatedSynonym",
"val": "deficiency of platelet glycoprotein 1b",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "giant platelet disease",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "glycoprotein Ib, Platelet, deficiency of"
},
{
"pred": "hasRelatedSynonym",
"val": "macrothrombocytopenia, familial Bernard-Soulier type",
"xrefs": [
"GARD:0002470"
]
}
],
"xrefs": [
{
"val": "DOID:2217"
},
{
"val": "GARD:2470"
},
{
"val": "MEDGEN:2212"
},
{
"val": "MESH:D001606"
},
{
"val": "MedDRA:10057473"
},
{
"val": "NANDO:2200656"
},
{
"val": "NCIT:C84595"
},
{
"val": "NORD:851"
},
{
"val": "OMIM:231200"
},
{
"val": "Orphanet:274"
},
{
"val": "SCTID:234478007"
},
{
"val": "UMLS:C0005129"
},
{
"val": "icd11.foundation:507309898"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009276",
"name": "Bernard-Soulier syndrome"
},
"entId": "MONDO:0009276",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009276",
"entType": "Disease",
"ldhId": "467874358",
"ldhIri": "https://genboree.org/cspec/Disease/id/467874358",
"modified": "2025-10-07T15:43:53.305Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V4O2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948594311200,
"agr": "HGNC:4440",
"alias_name": [
"platelet glycoprotein Ib beta chain"
],
"alias_symbol": [
"CD42c",
"GPIbbeta"
],
"ccds_id": [
"CCDS42980"
],
"cd": "CD42c",
"date_approved_reserved": "1991-11-21",
"date_modified": "2021-04-13",
"date_name_changed": "2018-04-23",
"ensembl_gene_id": "ENSG00000203618",
"entrez_id": "2812",
"gene_group": [
"CD molecules"
],
"gene_group_id": [
471
],
"hgnc_id": "HGNC:4440",
"location": "22q11.21",
"location_sortable": "22q11.21",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_478|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_478.xml"
],
"mane_select": [
"ENST00000366425.4",
"NM_000407.5"
],
"mgd_id": [
"MGI:107852"
],
"name": "glycoprotein Ib platelet subunit beta",
"omim_id": [
"138720"
],
"orphanet": 122241,
"prev_name": [
"glycoprotein Ib (platelet), beta polypeptide"
],
"pubmed_id": [
3422424
],
"refseq_accession": [
"NM_000407"
],
"rgd_id": [
"RGD:621050"
],
"status": "Approved",
"symbol": "GP1BB",
"ucsc_id": "uc062bnf.1",
"uniprot_ids": [
"P13224"
],
"uuid": "0ca03668-6920-451a-8120-493a4c2167b7",
"vega_id": "OTTHUMG00000150397"
}
},
"entId": "GP1BB",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4440",
"entType": "Gene",
"ldhId": "467828071",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828071",
"modified": "2021-10-14T11:36:40.599Z",
"modifier": "genbadmin",
"rev": "_h6SHyqu--O"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "082_nuclear_GP1BB",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0009276",
"preferredTitle": "Bernard-Soulier syndrome"
}
],
"gene": "GP1BB",
"preferredTranscript": "NM_000407.5"
}
],
"ns": "082",
"references": []
},
"entType": "RuleSet",
"ldhId": "1528071540",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528071540",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--L"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528071527",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528071527",
"modified": "2023-05-10T20:39:45.928Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyjy--D"
},
{
"entContent": {
"description": "Rule specifications for Bernard-Soulier syndrome associated with the GP9 gene.",
"namespace": "GN083",
"releaseNotes": "",
"shortTitle": "Platelet Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:28:28.440Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-02-10T15:01:50.473Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-17T19:00:42.735Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-10T20:40:46.282Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"083"
],
"title": "ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP9 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN083",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009276",
"lbl": "Bernard-Soulier syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009276"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/bernard_soulier_syndrome"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10057473"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/507309898"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2212"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D001606"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/234478007"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0005129"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_2217"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84595"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_274"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/231200"
}
],
"definition": {
"val": "Bernard Soulier syndrome (BSS) is an inherited platelet disorder characterized by mild to severe bleeding tendency, macrothrombocytopenia and absent ristocetin-induced platelet agglutination.",
"xrefs": [
"Orphanet:274"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Bernard - Soulier thrombopathy",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard Soulier syndrome",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome",
"xrefs": [
"DOID:2217",
"MONDO:Lexical",
"NCIT:C84595",
"OMIM:231200",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "Bernard-Soulier syndrome, type A1 (recessive)"
},
{
"pred": "hasExactSynonym",
"val": "Hemorrhagiparous thrombocytic dystrophy",
"xrefs": [
"Orphanet:274"
]
},
{
"pred": "hasExactSynonym",
"val": "giant platelet disorder, isolated"
},
{
"pred": "hasExactSynonym",
"val": "giant platelet syndrome",
"xrefs": [
"DOID:2217",
"Orphanet:274",
"icd11.foundation:507309898"
]
},
{
"pred": "hasExactSynonym",
"val": "hemorrhagic dystrophic thrombocytopenia",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasExactSynonym",
"val": "thrombopathy, Bernard-Soulier",
"xrefs": [
"DOID:2217"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BSS",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type A1"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type B"
},
{
"pred": "hasRelatedSynonym",
"val": "Bernard-Soulier syndrome, type C"
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein 1b, deficiency of",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Platelet glycoprotein Ib deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "Von Willebrand Factor receptor deficiency"
},
{
"pred": "hasRelatedSynonym",
"val": "bleeding disorder, Platelet-type, 1"
},
{
"pred": "hasRelatedSynonym",
"val": "deficiency of platelet glycoprotein 1b",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "giant platelet disease",
"xrefs": [
"GARD:0002470"
]
},
{
"pred": "hasRelatedSynonym",
"val": "glycoprotein Ib, Platelet, deficiency of"
},
{
"pred": "hasRelatedSynonym",
"val": "macrothrombocytopenia, familial Bernard-Soulier type",
"xrefs": [
"GARD:0002470"
]
}
],
"xrefs": [
{
"val": "DOID:2217"
},
{
"val": "GARD:2470"
},
{
"val": "MEDGEN:2212"
},
{
"val": "MESH:D001606"
},
{
"val": "MedDRA:10057473"
},
{
"val": "NANDO:2200656"
},
{
"val": "NCIT:C84595"
},
{
"val": "NORD:851"
},
{
"val": "OMIM:231200"
},
{
"val": "Orphanet:274"
},
{
"val": "SCTID:234478007"
},
{
"val": "UMLS:C0005129"
},
{
"val": "icd11.foundation:507309898"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009276",
"name": "Bernard-Soulier syndrome"
},
"entId": "MONDO:0009276",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009276",
"entType": "Disease",
"ldhId": "467874358",
"ldhIri": "https://genboree.org/cspec/Disease/id/467874358",
"modified": "2025-10-07T15:43:53.305Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V4O2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948596408300,
"agr": "HGNC:4444",
"alias_name": [
"platelet glycoprotein IX"
],
"alias_symbol": [
"CD42a",
"GPIX"
],
"ccds_id": [
"CCDS3055"
],
"cd": "CD42a",
"date_approved_reserved": "1991-03-04",
"date_modified": "2021-04-13",
"date_name_changed": "2016-01-14",
"ensembl_gene_id": "ENSG00000169704",
"entrez_id": "2815",
"gene_group": [
"CD molecules"
],
"gene_group_id": [
471
],
"hgnc_id": "HGNC:4444",
"location": "3q21.3",
"location_sortable": "03q21.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_477|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_477.xml"
],
"mane_select": [
"ENST00000307395.5",
"NM_000174.5"
],
"mgd_id": [
"MGI:1860137"
],
"name": "glycoprotein IX platelet",
"omim_id": [
"173515"
],
"orphanet": 122244,
"prev_name": [
"glycoprotein IX (platelet)"
],
"pubmed_id": [
2253772
],
"refseq_accession": [
"NM_000174"
],
"rgd_id": [
"RGD:1561601"
],
"status": "Approved",
"symbol": "GP9",
"ucsc_id": "uc003elm.3",
"uniprot_ids": [
"P14770"
],
"uuid": "8f623c19-fe31-4489-947f-d43c619b0b7d",
"vega_id": "OTTHUMG00000159944"
}
},
"entId": "GP9",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4444",
"entType": "Gene",
"ldhId": "467828076",
"ldhIri": "https://genboree.org/cspec/Gene/id/467828076",
"modified": "2021-10-14T11:36:40.599Z",
"modifier": "genbadmin",
"rev": "_h6SHyrW--c"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "083_nuclear_GP9",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0009276",
"preferredTitle": "Bernard-Soulier syndrome"
}
],
"gene": "GP9",
"preferredTranscript": "NM_000174.5"
}
],
"ns": "083",
"references": []
},
"entType": "RuleSet",
"ldhId": "1528072656",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528072656",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--N"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-09-19T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-04-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2020-06-12T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2020-06-16T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Platelet Disorders",
"shortBaseName": "Platelet",
"shortTitle": "Platelet Disorders VCEP",
"title": "Platelet Disorders Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50040",
"entIri": "https://www.clinicalgenome.org/affiliation/50040",
"entType": "Organization",
"ldhId": "135637652",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637652",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528072643",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528072643",
"modified": "2023-05-10T20:40:46.538Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHyjy--E"
},
{
"entContent": {
"approvedOn": "2023-07-17T13:46:49.999Z",
"description": "Rule specifications for antithrombin deficiency.",
"namespace": "GN084",
"releaseNotes": "All requested edits were made in this document and in the VCI, with exception of one. We would like the p.Cys29= variant to remain a VUS since there is only one benign code assigned. The point counting system is currently only being applied when conflicting rules codes are applied.",
"shortTitle": "Thrombosis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-09-30T19:36:49.338Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "leekristy",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-02-05T17:13:29.702Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-01-30T22:24:12.728Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "strande@email.unc.edu",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-05-10T20:24:41.947Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "leekristy",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-07-17T13:46:49.999Z"
},
"name": "Released"
}
],
"tagNameSpaces": [
"084"
],
"title": "ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN084",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "084_PP4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Please see attached guidance regarding the use of PP4/PS4 rule codes to properly assess eligibility. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count the proband used for the PP4 code for the PS4 code's proband count.",
"label": "PP4",
"ns": "084",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Proband must have an antithrombin activity level of \\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900918",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900918",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--F"
},
{
"entContent": {
"_uniqueProp": "084_BA1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BA1",
"ns": "084",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900914",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900914",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--I"
},
{
"entContent": {
"_uniqueProp": "084_BP5_nuclear_SERPINC1",
"additionalComments": "This rule code is not recommended for use at this time. There are other genes that can be associated with decreased antithrombin activity levels, such as genes associated with the congenital disorders of glycosylation.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP5",
"ns": "084",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0073",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0217",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900913",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900913",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--H"
},
{
"entContent": {
"_uniqueProp": "084_BS4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "084",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family, **OR** the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without _SERPINC1_ variant of interest.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels \\[\\< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)\\] within the same family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900902",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900902",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--G"
},
{
"entContent": {
"_uniqueProp": "084_BP6_nuclear_SERPINC1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "084",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900921",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900921",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--B"
},
{
"entContent": {
"_uniqueProp": "084_PP3_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Recommended splicing prediction tools are VarSEAK and SpliceAI. Recommended score for SpliceAI is greater or equal to 0.5.",
"label": "PP3",
"ns": "084",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, use of 2 independent _in silico_ splicing tools must predict a damaging impact.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900916",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900916",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--D"
},
{
"entContent": {
"_uniqueProp": "084_PP2_nuclear_SERPINC1",
"additionalComments": "Not applicable due to presence of benign variation throughout the SERPINC1 gene. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "084",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900915",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900915",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo6---"
},
{
"entContent": {
"_uniqueProp": "084_PVS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "084",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use decision tree as per SVI WG with specified “regions critical to protein function”.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900912",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900912",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--E"
},
{
"entContent": {
"_uniqueProp": "084_PP1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PP1",
"ns": "084",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use there are 7 or more meioses across more than one family.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use there are 4-6 meioses across one or more families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use when there are 2-3 meioses across one or more families.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900910",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900910",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpC--C"
},
{
"entContent": {
"_uniqueProp": "084_BP4_nuclear_SERPINC1",
"additionalComments": "Not using at this time but will note CADD and SpliceAI scores and consider use during pilot testing. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP4",
"ns": "084",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use this code for missense variants with a REVEL score of \\< 0.30 and no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools, or for non-canonical intronic variants with no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900909",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900909",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--D"
},
{
"entContent": {
"_uniqueProp": "084_PS2_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Any proband must meet the PP4 defined antithrombin deficiency laboratory phenotype (see PP4/PS4 description below).",
"label": "PS2",
"ns": "084",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900906",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900906",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpC--B"
},
{
"entContent": {
"_uniqueProp": "084_PM6_nuclear_SERPINC1",
"additionalComments": "Use the PS2 code in lieu of using this code for de novo variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "084",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900903",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900903",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo2--Q"
},
{
"entContent": {
"_uniqueProp": "084_BS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Common founder SERPINC1 variants are excluded from eligibility of the BS1 code. The list of variants will likely grow over time, but currently consists of the SERPINC1 c.218C>T; p.Pro73Leu (PMID:23910795), SERPINC1 c.236G>A; p.Arg79His (AT Padua), SERPINC1 c.439A>G; p.Thr147Ala (PMID:32920809) and SERPINC1 c.1246G>T ; SERPINC1 p.Ala416Ser (AT Cambridge II); SERPINC1 p.Leu131Phe (PMID:26748602) variants.",
"label": "BS1",
"ns": "084",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900895",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900895",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo2--P"
},
{
"entContent": {
"_uniqueProp": "084_PS1_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Use caution not to compare variants being curated to variants that are potential cryptic slice sites.",
"label": "PS1",
"ns": "084",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use with no specification except comparison variant must be classified as pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use with no specification except comparison variant must be classified as likely pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900904",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900904",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--B"
},
{
"entContent": {
"_uniqueProp": "084_BP1_nuclear_SERPINC1",
"additionalComments": "This rule code does not apply to the SERPINC1 gene, as missense and truncating variants account for disease.\n",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP1",
"ns": "084",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900901",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900901",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpe--F"
},
{
"entContent": {
"_uniqueProp": "084_PP5_nuclear_SERPINC1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "084",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900922",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900922",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--F"
},
{
"entContent": {
"_uniqueProp": "084_PM2_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM2",
"ns": "084",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Disease-specific",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code for variants with a popmax MAF of \\<0.00002 in gnomAD.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900920",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900920",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--A"
},
{
"entContent": {
"_uniqueProp": "084_BP3_nuclear_SERPINC1",
"additionalComments": "There are no known repetitive regions in the SERPINC1 gene without a known function. ",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "084",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900907",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900907",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--A"
},
{
"entContent": {
"_uniqueProp": "084_PM5_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Use caution not to compare variants being curated to variants that are potential cryptic slice sites.",
"label": "PM5",
"ns": "084",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use code when previously reported variant reaches a pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use code when previously reported variant reaches a likely pathogenic classification using the _SERPINC1_ rule specifications from the Thrombosis VCEP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900900",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900900",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--A"
},
{
"entContent": {
"_uniqueProp": "084_PM4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "084",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"None"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "No specification",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0059",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900898",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900898",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa---"
},
{
"entContent": {
"_uniqueProp": "084_BS2_nuclear_SERPINC1",
"additionalComments": "Not applicable due to the incomplete penetrance seen in VWD. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BS2",
"ns": "084",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels \\[> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900897",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900897",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpC--A"
},
{
"entContent": {
"_uniqueProp": "084_PM3_nuclear_SERPINC1",
"additionalComments": "Variants in this gene are being curated as a dominant condition, so this rule code does not apply.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "084",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900896",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900896",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpW--K"
},
{
"entContent": {
"_uniqueProp": "084_PM1_nuclear_SERPINC1",
"additionalComments": "Rule does not apply due to benign variation being present throughout the gene and no known hotspots.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "084",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)1, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79) and variants involving reactive site residues (Ala414 and Ala416)2.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900919",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900919",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxo6--_"
},
{
"entContent": {
"_uniqueProp": "084_BP7_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP7",
"ns": "084",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use tools VarSEAK and Splice AI to rule out a predicted splicing effect. Evolutionary conservation is defined as a PhyloP \\< 0.1 **OR** the reference nucleotide is present in 3 mammals or 1 primate.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900917",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900917",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--E"
},
{
"entContent": {
"_uniqueProp": "084_PS4_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "This code requires the use of proband points. Please see attached guidance on tallying proband points for this phenotype. Do not apply this code for variants that meet BS1 or BA1 criteria. Do not count proband used for PP4 in this code's proband count.",
"label": "PS4",
"ns": "084",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900911",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900911",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--C"
},
{
"entContent": {
"_uniqueProp": "084_PS3_nuclear_SERPINC1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"instructionsToUse": "Model organism do not tend to recapitulate the phenotype of interest and are not used for curation.",
"label": "PS3",
"ns": "084",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:\n\n - _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:\n\n* Antithrombin activity levels measured by FXa inhibition activity assay\n* Antithrombin activity levels measured by thrombin inhibition activity assay\n\nOR\n\n\\- _In vitro_ functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:\n\n* Antithrombin antigen levels measured by ELISA\n * Immunofluorescence assay – intracellular retention and secretion defects\n\nOR\n\n\\- _In vivo_ studies demonstrating rescue of antithrombin levels would be considered, but no studies are known to be available at this time.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900908",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900908",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--B"
},
{
"entContent": {
"_uniqueProp": "084_BP2_nuclear_SERPINC1",
"additionalComments": "Do not use as individuals can be homozygous for SERPINC1 variants.",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "084",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "not approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Disease-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This rule can be applied when a _SERPINC1_ variant is _in cis_ with another pathogenic _SERPINC1_ variant. The pathogenic variant must be evaluated using ClinGen _SERPINC1_ specified rules. This rule cannot be applied to a variant _in trans_ with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900905",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900905",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpK--C"
},
{
"entContent": {
"_uniqueProp": "084_BS3_nuclear_SERPINC1",
"additionalComments": "There are no available assays or model organisms that can recapitulate disease, and in vitro studies cannot dependably rule out pathogenicity.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"SERPINC1"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "084",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "not approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "not approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0072",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0100",
"instructionsToUse": "",
"status": "not approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0085",
"instructionsToUse": "",
"status": "not approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1611900899",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1611900899",
"modified": "2023-07-17T13:46:50.648Z",
"modifier": "leekristy",
"rev": "_h6SHxpa--_"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0013144",
"lbl": "hereditary antithrombin deficiency",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0013144"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/antithrombin_iii_deficiency"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/75781"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D020152"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/36351005"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0272375"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3755"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_82"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/613118"
}
],
"definition": {
"val": "A rare, genetic, hematological disease characterized by decreased levels of antithrombin activity in plasma resulting in impaired inactivation of thrombin and factor Xa. Patients have an increased risk for venous thromboembolism, usually in the deep veins of the arms, legs and pulmonary system and, on occasion, in other venous territories (e.g. cerebral veins or sinus, mesenteric, portal, hepatic, renal and/or retinal veins).",
"xrefs": [
"Orphanet:82"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "AT III deficiency",
"xrefs": [
"DOID:3755"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "AT3D",
"xrefs": [
"MONDO:Lexical",
"OMIM:613118"
]
},
{
"pred": "hasExactSynonym",
"val": "Antithrombin Deficiency",
"xrefs": [
"NORD:791"
]
},
{
"pred": "hasExactSynonym",
"val": "antithrombin 3 deficiency",
"xrefs": [
"OMIM:613118"
]
},
{
"pred": "hasExactSynonym",
"val": "antithrombin III deficiency",
"xrefs": [
"DOID:3755",
"MONDO:Lexical"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital AT-III deficiency",
"xrefs": [
"GARD:0006148"
]
},
{
"pred": "hasExactSynonym",
"val": "congenital antithrombin III deficiency",
"xrefs": [
"GARD:0006148"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary antithrombin deficiency",
"xrefs": [
"GARD:0006148"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary thrombophilia due to congenital antithrombin 3 deficiency",
"xrefs": [
"Orphanet:82"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary thrombophilia due to congenital antithrombin deficiency",
"xrefs": [
"DOID:3755",
"Orphanet:82"
]
},
{
"pred": "hasExactSynonym",
"val": "inherited antithrombin deficiency",
"xrefs": [
"GARD:0006148"
]
},
{
"pred": "hasExactSynonym",
"val": "thrombophilia 7 due to antithrombin III deficiency"
},
{
"pred": "hasExactSynonym",
"val": "thrombophilia due to antithrombin 3 deficiency",
"xrefs": [
"OMIM:613118"
]
},
{
"pred": "hasExactSynonym",
"val": "thrombophilia due to antithrombin III deficiency",
"xrefs": [
"GARD:0006148"
]
}
],
"xrefs": [
{
"val": "DOID:3755"
},
{
"val": "GARD:6148"
},
{
"val": "ICD9:286.9"
},
{
"val": "MEDGEN:75781"
},
{
"val": "MESH:D020152"
},
{
"val": "NORD:791"
},
{
"val": "OMIM:613118"
},
{
"val": "Orphanet:82"
},
{
"val": "SCTID:36351005"
},
{
"val": "UMLS:C0272375"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0013144",
"name": "hereditary antithrombin deficiency"
},
"entId": "MONDO:0013144",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0013144",
"entType": "Disease",
"ldhId": "467885201",
"ldhIri": "https://genboree.org/cspec/Disease/id/467885201",
"modified": "2025-10-07T15:44:55.747Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7W1F6--A"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056962724921300,
"agr": "HGNC:775",
"alias_name": [
"antithrombin III",
"signal peptide antithrombin part 1",
"coding sequence signal peptide antithrombin part 1",
"antithrombin (aa 375-432)"
],
"alias_symbol": [
"ATIII",
"MGC22579"
],
"ccds_id": [
"CCDS1313"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2016-04-06",
"ena": [
"X68793"
],
"ensembl_gene_id": "ENSG00000117601",
"entrez_id": "462",
"gene_group": [
"Serpin peptidase inhibitors"
],
"gene_group_id": [
739
],
"hgnc_id": "HGNC:775",
"iuphar": "objectId:2632",
"location": "1q25.1",
"location_sortable": "01q25.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Antithrombin III mutation database|http://www1.imperial.ac.uk/departmentofmedicine/divisions/experimentalmedicine/haematology/coag/antithrombin/",
"LRG_577|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_577.xml"
],
"mane_select": [
"ENST00000367698.4",
"NM_000488.4"
],
"merops": "I04.018",
"mgd_id": [
"MGI:88095"
],
"name": "serpin family C member 1",
"omim_id": [
"107300"
],
"orphanet": 118609,
"prev_name": [
"serine (or cysteine) proteinase inhibitor, clade C (antithrombin), member 1",
"serpin peptidase inhibitor, clade C (antithrombin), member 1"
],
"prev_symbol": [
"AT3"
],
"pubmed_id": [
3979120,
24172014
],
"refseq_accession": [
"NM_000488"
],
"rgd_id": [
"RGD:1307404"
],
"status": "Approved",
"symbol": "SERPINC1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001gjt.4",
"uniprot_ids": [
"P01008"
],
"uuid": "9384cf46-ff53-44e4-ac62-ddaaba333da7",
"vega_id": "OTTHUMG00000037276"
}
},
"entId": "SERPINC1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:775",
"entType": "Gene",
"ldhId": "467855776",
"ldhIri": "https://genboree.org/cspec/Gene/id/467855776",
"modified": "2021-10-14T11:37:07.374Z",
"modifier": "genbadmin",
"rev": "_h6SHz86--O"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "084_nuclear_SERPINC1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0013144",
"preferredTitle": "antithrombin III deficiency"
}
],
"gene": "SERPINC1",
"preferredTranscript": "NM_000488.4"
}
],
"ns": "084",
"references": [
{
"auths": [
"Kottke-Marchant K",
"Duncan A"
],
"doiStr": "10.5858/2002-126-1326-AD",
"id": "12421140",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1326-36.",
"source": "Arch Pathol Lab Med",
"title": "Antithrombin deficiency: issues in laboratory diagnosis.",
"vol": "126",
"year": "2002"
},
{
"auths": [
"Perry DJ",
"Carrell RW"
],
"doiStr": "",
"id": "2615648",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 239-43.",
"source": "Mol Biol Med",
"title": "CpG dinucleotides are \"hotspots\" for mutation in the antithrombin III gene. Twelve variants identified using the polymerase chain reaction.",
"vol": "6",
"year": "1989"
},
{
"auths": [
"Orlando C",
"de la Morena-Barrio B",
"et al."
],
"doiStr": "10.1055/s-0040-1716531",
"id": "32920809",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. 182-191.",
"source": "Thromb Haemost",
"title": "Antithrombin p.Thr147Ala: The First Founder Mutation in People of African Origin Responsible for Inherited Antithrombin Deficiency.",
"vol": "121",
"year": "2021"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS2_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS4_Supporting",
"BP2",
"BP4",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1528074035",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528074035",
"modified": "2023-07-17T13:46:50.506Z",
"modifier": "leekristy",
"rev": "_h6SHyTS--j"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "Thrombosis",
"approval": {
"step1": {
"approvalDate": "2020-03-01T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-03-01T00:00:00.000Z",
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2023-06-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Thrombosis",
"shortTitle": "Thrombosis VCEP",
"title": "Thrombosis Variant Curation Expert Panel ",
"type": "Variant Curation Expert Panel"
},
"entId": "50064",
"entIri": "https://clinicalgenome.org/affiliation/50064",
"entType": "Organization",
"ldhId": "647188070",
"ldhIri": "https://genboree.org/cspec/Organization/id/647188070",
"modified": "2023-07-13T16:10:42.371Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--H"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528074022",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528074022",
"modified": "2023-09-29T15:16:49.944Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykS--Q"
},
{
"entContent": {
"approvedOn": "2023-10-11T00:08:05.287Z",
"description": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines ",
"namespace": "GN085",
"releaseNotes": "Upgrade initiation codon variants from PVS1\\_Moderate to PVS1\\_Strong on the basis that next methionine is Met71 and multiple variants not found in gnomAD have been reported in patients meeting diagnostic criteria for MODY (PMID: 23348805)",
"releasedUnderRevision": true,
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-03T19:43:58.274Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-09-15T17:57:42.509Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-10T20:03:39.521Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-10-11T00:08:05.287Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-11T00:09:15.508Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "tonipollin",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-06-25T18:51:29.117Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"085"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0",
"version": "2.0.0",
"versioned": true
},
"entId": "GN085",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "085_BP4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "085",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2[3](#pmid_30661751),[4](#pmid_32123317).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887515",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887515",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--A"
},
{
"entContent": {
"_uniqueProp": "085_BS2_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "085",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887509",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887509",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2---"
},
{
"entContent": {
"_uniqueProp": "085_PP2_nuclear_HNF4A",
"additionalComments": "While missense variants in HNF4A are a common mechanism of monogenic diabetes, and the constraint score for HNF4A (gene) is 1.81, the MDEP does not support using this criterion at this time. ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "085",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887504",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887504",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--E"
},
{
"entContent": {
"_uniqueProp": "085_PS2_nuclear_HNF4A",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) and negative HNF1A testing). To obtain standard points (“phenotype consistent with gene but not highly specific”), the phenotype of the patient must include diabetes. Probands (and/or family members when assessing segregation for PP1) with evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency will be excluded when assessing criteria that includes phenotype information. Such evidence includes the following:One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 7,8,9,10). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)(Ref 11,12) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 8,9)",
"label": "PS2",
"ns": "085",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887494",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887494",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--B"
},
{
"entContent": {
"_uniqueProp": "085_PVS1_nuclear_HNF4A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"label": "PVS1",
"ns": "085",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use _HNF4A_ PVS1 decision tree.\n\n* Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD[1](#pmid_24274751)\n * The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP. There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1\\_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”\n * Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _HNF4A_ PVS1 decision tree.\n\n* “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\\_Strong \n * Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\\_Strong\n* Apply PVS1\\_Strong to initiation codon variants. MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2\\_Supporting + PP4\\_Moderate + PP1\\_Strong + PVS1\\_Moderate (c.1delA); c.1delA: PM2\\_Supporting + PP1 + PP4\\_Moderate + PVS1\\_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _HNF4A_ PVS1 decision tree.\n\nApply PVS1\\_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887492",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887492",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpW--I"
},
{
"entContent": {
"_uniqueProp": "085_BP7_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "085",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887517",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887517",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--H"
},
{
"entContent": {
"_uniqueProp": "085_BP2_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "085",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887513",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887513",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--F"
},
{
"entContent": {
"_uniqueProp": "085_BS1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "If there is a Popmax Filtering AF for both exomes and genomes, use the one with the larger denominator.",
"label": "BS1",
"ns": "085",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:30,000 (≥0.0033% or 0.000033).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887508",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887508",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--G"
},
{
"entContent": {
"_uniqueProp": "085_PP4_nuclear_HNF4A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "MODY probability calculator result of ≥50% chance of testing positive (https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF1A genetic analysis, given the similarities in phenotypes between HNF1A-MODY and HNF4A-MODY. Clinical judgement may need to be used when applying this criterion, as the MODY Probability Calculator is not as reliable for non-European ancestry individuals or people diagnosed >35. For example, use of PP4 is acceptable in the absence of HNF1A analysis when the MPC is >50% and the phenotype is specific to HNF4A, for example someone in the family with neonatal hypoglycemia that is responsive to diazoxide or hyperinsulinemic hypoglycemia. If individual was tested due to neonatal hypoglycemia, PP4 can be used if ABCC8 and KCNJ11 testing are negative (no MODY Probability Calculator result required). Certain assumptions can be made in order to use the MODY probability calculator. Specific clinical info about parents not given but lab/literature states “Family history of diabetes”, click “Parent with diabetes” in calculator. If no information about family history of diabetes is provided, run the calculator in both conditions (yes/no) and document whether this makes a difference in overall probability score. Weight/Height/BMI not given but lab/literature states patient is “lean”, enter BMI of 30. HbA1c is not provided, enter 6% and 10% and document whether this makes a difference in overall probability score. Treatment information is not provided, cannot use calculator. ",
"label": "PP4",
"ns": "085",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Phenotype: MODY Probability Calculator result ≥50% chance of testing positive[6](#url_187f5e4a-1941-5c2d-9c9f-1dc999cc5454) AND negative _HNF1A_ testing AND presence of at least one additional feature characteristic of \\__HNF4A_\\_-MODY: \n\n* Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis \n* Personal or family history of persistent neonatal hypoglycemia \n* Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia \n* Response to low-dose SU (extreme response- hypoglycemia) \n* Biochemical/Molecular phenotypic evidence from patient cell lines \n* Fanconi phenotype in conjunction with c.187C>T p.R63W",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "MODY Probability Calculator (MPC)6 result ≥50% chance of testing positive AND negative _HNF1A_ testing",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887506",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887506",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--F"
},
{
"entContent": {
"_uniqueProp": "085_PM6_nuclear_HNF4A",
"additionalComments": "Subsumed by PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "085",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887502",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887502",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpy--C"
},
{
"entContent": {
"_uniqueProp": "085_PM2_nuclear_HNF4A",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1. ",
"label": "PM2",
"ns": "085",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887498",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887498",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--C"
},
{
"entContent": {
"_uniqueProp": "085_PS3_nuclear_HNF4A",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "See list of approved functional studies and guidelines for interpretation of data.",
"label": "PS3",
"ns": "085",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "List of approved functional studies and guidelines for interpretation:\n\n* EMSA for DNA binding\n * “Decreased function” is defined as activity less than 60% of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “Decreased function” is defined as activity less than 60% of wildtype \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).\n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique. Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.\n* To use PS3\\_Supporting, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3\\_Supporting.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887495",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887495",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpy--_"
},
{
"entContent": {
"_uniqueProp": "085_PP5_nuclear_HNF4A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "085",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887519",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887519",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--B"
},
{
"entContent": {
"_uniqueProp": "085_BP1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "085",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887512",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887512",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpW--L"
},
{
"entContent": {
"_uniqueProp": "085_BA1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "If there is a Popmax Filtering AF for both exomes and genomes, use the one with the larger denominator.",
"label": "BA1",
"ns": "085",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887507",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887507",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpy--D"
},
{
"entContent": {
"_uniqueProp": "085_PP3_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "085",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2 [4](#pmid_32123317),[3](#pmid_30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887505",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887505",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpW--K"
},
{
"entContent": {
"_uniqueProp": "085_PM3_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM3",
"ns": "085",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887499",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887499",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--D"
},
{
"entContent": {
"_uniqueProp": "085_BS4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "085",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who have MPC6 score ≥50% (i.e., genotype negative, phenotype positive).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887511",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887511",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxp2--_"
},
{
"entContent": {
"_uniqueProp": "085_PM4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "085",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For single amino acid deletions, use as supporting level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For single amino acid deletions/insertions, use as supporting level of evidence",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887500",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887500",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--m"
},
{
"entContent": {
"_uniqueProp": "085_PM1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM1",
"ns": "085",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation[2](#pmid_18829458) \n\n* Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112 \n* Homodimer: Arg75, Gln89, Glu111, Asp113 \n* Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain transcription factor binding sites in the promoter (see below for details).\n\n* Promoter region: \n * c.-132 to c.-151 (HNF6/OC2 and IPF1 binding sites) \n * c.-169 to c.-181 (HNF1A/HNF1B binding sites)\n* DNA binding: \n * codons 37-113 (NM\\_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of _HNF4A_[2](#pmid_18829458) shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)\n* Ligand binding: \n * codons 180-220 and 300-350 \n * (NM\\_175914.4:c.538G-658G p.Ala180-Val220) \n * (NM\\_175914.4:c.898T-1048G p.Tyr300-Glu350)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887497",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887497",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--C"
},
{
"entContent": {
"_uniqueProp": "085_PS1_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "085",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887493",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887493",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpW--J"
},
{
"entContent": {
"_uniqueProp": "085_BP6_nuclear_HNF4A",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "085",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887518",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887518",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--H"
},
{
"entContent": {
"_uniqueProp": "085_BP5_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "085",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887516",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887516",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--o"
},
{
"entContent": {
"_uniqueProp": "085_BP3_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "085",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887514",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887514",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--G"
},
{
"entContent": {
"_uniqueProp": "085_BS3_nuclear_HNF4A",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) it cannot count as BS3. ",
"label": "BS3",
"ns": "085",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "List of approved functional studies and guidelines for interpretation of data.\n\n* EMSA for DNA binding \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.\n* Luciferase assays for transactivation \n * “No functional impact” is defined as ≥75% activity of wildtype \n * Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.\n* Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively). \n * Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique. Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887510",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887510",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--n"
},
{
"entContent": {
"_uniqueProp": "085_PP1_nuclear_HNF4A",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "Variable penetrance and phenocopies complicate co-segregation studies. The presence of type 1 and type 2 diabetes phenocopies and significance of variants in unaffected individuals as defined above will need to be considered. If a family member(s) shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see below), do not include them in PP1 calculation.One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 7,8,9,10). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 11,12) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 8,9). Unaffected family members without the variant under assessment can also be used in segregation analysis(Ref 5). An individual is considered “unaffected” if over age 70 and non-diabetic (based on Exeter work (Ref 13) which shows penetrance of HNF4A-MODY at 98% by age 70).",
"label": "PP1",
"ns": "085",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\> 1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\> 1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning[5](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\> 1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887503",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887503",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--E"
},
{
"entContent": {
"_uniqueProp": "085_PM5_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "085",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887501",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887501",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--D"
},
{
"entContent": {
"_uniqueProp": "085_PS4_nuclear_HNF4A",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"HNF4A"
],
"geneType": "nuclear",
"instructionsToUse": "The phenotype of the patient must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency (see above) considered as exclusionary. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). ",
"label": "PS4",
"ns": "085",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2\\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690) \n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 unrelated occurrences = Moderate. Variant should meet PM2\\_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.\n\n* One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)[7](#pmid_21395678),[8](#pmid_28701371),[9](#pmid_30409810),[10](#pmid_31704690)\n* Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (\\<200pmol/L or 0.6ng/mL)[11](#pmid_30225972),[12](#pmid_23771925) or urinary C-peptide/creatinine ratio \\<0.2 nmol/mmol[8](#pmid_28701371),[9](#pmid_30409810)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533887496",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533887496",
"modified": "2023-10-11T00:08:05.992Z",
"modifier": "tonipollin",
"rev": "_h6SHxpy--B"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1392102"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
"https://doi.org/10.2337/dci20-0065"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "monogenic diabetes",
"xrefs": [
"NCIT:C129739"
]
},
{
"pred": "hasExactSynonym",
"val": "rare genetic diabetes mellitus",
"xrefs": [
"Orphanet:183625"
]
}
],
"xrefs": [
{
"val": "EFO:1001511"
},
{
"val": "MEDGEN:1392102"
},
{
"val": "NCIT:C129739"
},
{
"val": "Orphanet:183625"
},
{
"val": "UMLS:C3888631"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://genboree.org/cspec/Disease/id/467884025",
"modified": "2025-10-07T15:45:43.374Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xjrq---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949438414800,
"agr": "HGNC:5024",
"alias_symbol": [
"NR2A1",
"HNF4"
],
"ccds_id": [
"CCDS13330",
"CCDS42876",
"CCDS68131",
"CCDS46605",
"CCDS13331",
"CCDS46604",
"CCDS74728"
],
"date_approved_reserved": "1998-04-20",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-18",
"ena": [
"X76930"
],
"ensembl_gene_id": "ENSG00000101076",
"entrez_id": "3172",
"gene_group": [
"MicroRNA protein coding host genes",
"Hepatocyte nuclear factor 4 family"
],
"gene_group_id": [
1691,
2085
],
"hgnc_id": "HGNC:5024",
"iuphar": "objectId:608",
"location": "20q13.12",
"location_sortable": "20q13.12",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/HNF4A",
"LRG_483|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_483.xml"
],
"mane_select": [
"ENST00000316099.9",
"NM_000457.5"
],
"mgd_id": [
"MGI:109128"
],
"name": "hepatocyte nuclear factor 4 alpha",
"omim_id": [
"600281"
],
"orphanet": 122455,
"prev_symbol": [
"TCF14",
"MODY",
"MODY1"
],
"pubmed_id": [
7926813,
9048927
],
"refseq_accession": [
"NM_000457"
],
"rgd_id": [
"RGD:2810"
],
"status": "Approved",
"symbol": "HNF4A",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002xlt.4",
"uniprot_ids": [
"P41235"
],
"uuid": "bc909d3c-f1c0-46d8-8340-d884a4ede4c2",
"vega_id": "OTTHUMG00000032531"
}
},
"entId": "HNF4A",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5024",
"entType": "Gene",
"ldhId": "467829602",
"ldhIri": "https://genboree.org/cspec/Gene/id/467829602",
"modified": "2021-10-14T11:36:42.130Z",
"modifier": "genbadmin",
"rev": "_h6SHz----C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "085_nuclear_HNF4A",
"geneType": "nuclear",
"generalComments": "Upgrade initiation codon variants from PVS1_Moderate to PVS1_Strong on the basis that next methionine is Met71 and multiple variants not found in gnomAD have been reported in patients meeting diagnostic criteria for MODY (PMID: 23348805) ",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0015967",
"preferredTitle": "monogenic diabetes"
}
],
"gene": "HNF4A",
"preferredTranscript": "NM_175914.5"
}
],
"ns": "085",
"references": [
{
"auths": [
"Popp MW",
"Maquat LE"
],
"doiStr": "10.1146/annurev-genet-111212-133424",
"id": "24274751",
"iss": "",
"namespace": "pmid",
"pages": "p. 139-65.",
"source": "Annu Rev Genet",
"title": "Organizing principles of mammalian nonsense-mediated mRNA decay.",
"vol": "47",
"year": "2013"
},
{
"auths": [
"Lu P",
"Rha GB",
"et al."
],
"doiStr": "10.1074/jbc.M806213200",
"id": "18829458",
"iss": "(48)",
"namespace": "pmid",
"pages": "p. 33685-97.",
"source": "J Biol Chem",
"title": "Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4alpha. Diabetes gene product.",
"vol": "283",
"year": "2008"
},
{
"auths": [
"Jaganathan K",
"Kyriazopoulou Panagiotopoulou S",
"et al."
],
"doiStr": "10.1016/j.cell.2018.12.015",
"id": "30661751",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 535-548.e24.",
"source": "Cell",
"title": "Predicting Splicing from Primary Sequence with Deep Learning.",
"vol": "176",
"year": "2019"
},
{
"auths": [
"Wai HA",
"Lord J",
"et al."
],
"doiStr": "10.1038/s41436-020-0766-9",
"id": "32123317",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1005-1014.",
"source": "Genet Med",
"title": "Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.",
"vol": "22",
"year": "2020"
},
{
"auths": [
"Jarvik GP",
"Browning BL"
],
"doiStr": "10.1016/j.ajhg.2016.04.003",
"id": "27236918",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1077-1081.",
"source": "Am J Hum Genet",
"title": "Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants.",
"vol": "98",
"year": "2016"
},
{
"id": "187f5e4a-1941-5c2d-9c9f-1dc999cc5454",
"namespace": "url",
"value": "https://www.diabetesgenes.org/mody-probability-calculator/"
},
{
"auths": [
"McDonald TJ",
"Colclough K",
"et al."
],
"doiStr": "10.1111/j.1464-5491.2011.03287.x",
"id": "21395678",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1028-33.",
"source": "Diabet Med",
"title": "Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.",
"vol": "28",
"year": "2011"
},
{
"auths": [
"Shields BM",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc17-0224",
"id": "28701371",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 1017-1025.",
"source": "Diabetes Care",
"title": "Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.",
"vol": "40",
"year": "2017"
},
{
"auths": [
"Patel KA",
"Weedon MN",
"et al."
],
"doiStr": "10.2337/dc18-0373",
"id": "30409810",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. e16-e17.",
"source": "Diabetes Care",
"title": "Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes.",
"vol": "42",
"year": "2019"
},
{
"auths": [
"Carlsson A",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc19-0747",
"id": "31704690",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 82-89.",
"source": "Diabetes Care",
"title": "Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study.",
"vol": "43",
"year": "2020"
},
{
"auths": [
"Hattersley AT",
"Greeley SAW",
"et al."
],
"doiStr": "10.1111/pedi.12772",
"id": "30225972",
"iss": "",
"namespace": "pmid",
"pages": "p. 47-63.",
"source": "Pediatr Diabetes",
"title": "ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.",
"vol": "19 Suppl 27",
"year": "2018"
},
{
"auths": [
"Pihoker C",
"Gilliam LK",
"et al."
],
"doiStr": "10.1210/jc.2013-1279",
"id": "23771925",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 4055-62.",
"source": "J Clin Endocrinol Metab",
"title": "Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.",
"vol": "98",
"year": "2013"
},
{
"auths": [
"Patel KA",
"Kettunen J",
"et al."
],
"doiStr": "10.1038/s41467-017-00895-9",
"id": "29026101",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 888.",
"source": "Nat Commun",
"title": "Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.",
"vol": "8",
"year": "2017"
},
{
"auths": [
"Hamilton AJ",
"Bingham C",
"et al."
],
"doiStr": "10.1136/jmedgenet-2013-102066",
"id": "24285859",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 165-9.",
"source": "J Med Genet",
"title": "The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.",
"vol": "51",
"year": "2014"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM1",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM1_Supporting",
"PM2_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule20"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1528338164",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528338164",
"modified": "2023-10-11T00:08:05.886Z",
"modifier": "tonipollin",
"rev": "_h6SHyTS--q"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-11-21T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-06-04T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-08-18T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Monogenic Diabetes",
"shortBaseName": "Diabetes",
"shortTitle": "Monogenic Diabetes VCEP",
"title": "Monogenic Diabetes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50016",
"entIri": "http://clinicalgenome.org/affiliation/50016",
"entType": "Organization",
"ldhId": "135637640",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637640",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--I"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528338151",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528338151",
"modified": "2023-10-11T00:08:05.798Z",
"modifier": "tonipollin",
"rev": "_h6SHykC--M"
},
{
"entContent": {
"approvedOn": "2023-08-11T16:06:02.452Z",
"description": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version",
"namespace": "GN086",
"releaseNotes": "Indicated that gnomAD v.3.1.2 genomes should be used for variants not covered in v2.1.1 exomes for PM2\\_Supporting/BA1/BS1 based on sample size and consistent with gnomAD guidance\n\nInheritance pattern for GCK/monogenic diabetes has been updated to “Semidominant\" per what has already been recommended and approved by the SVI.",
"releasedUnderRevision": true,
"shortTitle": "Monogenic Diabetes Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-03T19:46:15.093Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-05T21:31:26.044Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-11T15:50:34.569Z"
},
"name": "Approved For Release"
},
{
"current": false,
"event": {
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-08-11T16:06:02.452Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-12-03T02:45:17.691Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-09T15:59:06.054Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-09T17:46:51.251Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"086"
],
"title": "ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0",
"version": "1.3.0",
"versioned": true
},
"entId": "GN086",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "086_BS3_nuclear_GCK",
"additionalComments": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variants the patient has) it cannot count as BS3. ",
"label": "BS3",
"ns": "086",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0226",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0225",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.\n\nEvidence of no impact on function:\n\n* Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3\\_Supporting \n* Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3\n\nGloyn, et al. 2005 [5](#pmid_15677479); Beer, et al. 2012 [6](#pmid_22611063); Raimondo, et al. 2014 [7](#pmid_25015100); Gloyn, et al. (2004)12.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888297",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888297",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--F"
},
{
"entContent": {
"_uniqueProp": "086_PP4_nuclear_GCK",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).\nCertain assumptions can be made in order to use the MODY probability calculator: \n* Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. \n* No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. \n* HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. \n* Treatment information is not provided: Cannot use calculator. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Negative testing of other genes not necessary because phenotype is very specific. Sixty percent of patients with GCK-MODY phenotype will test positive. There is a small chance that patient has HNF1A- or HNF4A-MODY in the early stages of disease (can get info about likelihood from family history). About 1% of patients with GCK-MODY will have deletions or other variants (e.g., promoter) that are not identified via Sanger sequencing- consider testing via NGS or other technology. For patients tested because of neonatal diabetes, PP4 can be applied if there has been negative testing for major monogenic causes for neonatal diabetes. These include ABCC8, KCNJ11, and INS. In consanguineous cases, EIF2AK3 should be tested as well",
"label": "PP4",
"ns": "086",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0239",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "002",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:\n\n* PP4 phenotype found in pediatric patient (prepubertal or \\<10 years) (incidentally) AND \n * Not treated with insulin AND antibody negative \n * OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years\n* Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) \n* OGTT with minimal increment \\<3 mmol/l (54 mg/dl) \n* Antibody negative \n* Macrosomia in normoglycemic offspring of hyperglycemic gestational parent\n* Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. \n* Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888293",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888293",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--L"
},
{
"entContent": {
"_uniqueProp": "086_PM2_nuclear_GCK",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend using as supporting level of evidence (PM2_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1. Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator.",
"label": "PM2",
"ns": "086",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0231",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0044",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0013",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "gnomAD 2.1.1\\* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888285",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888285",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--D"
},
{
"entContent": {
"_uniqueProp": "086_PS2_nuclear_GCK",
"additionalComments": "To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2. ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "To obtain maximum points (“phenotype highly specific for gene”), patient must meet criteria for PP4. To obtain standard points (“phenotype consistent with gene but not highly specific”), the phenotype of the patient must include hyperglycemia or impaired fasting glucose, with no evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency. Exclusionary evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency includes the following: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15, 16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 16, 17). We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to consider a parent unaffected; fasting glucose must be tested and found to be within normal limits (<100 mg/dl = 5.5 mmol/L) or HbA1c <=5.5% (37 mmol/mol) since the GCK range was 5.6 - 7.6% (38 – 60 mmol/mol)(Ref 19). Presence of clinically significant diabetes complications in anyone with the variant is an exclusion.",
"label": "PS2",
"ns": "086",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0241",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. \n.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0043",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888281",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888281",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--D"
},
{
"entContent": {
"_uniqueProp": "086_BP5_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP5",
"ns": "086",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0218",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0216",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A variant in another monogenic diabetes gene is P/LP.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888303",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888303",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--I"
},
{
"entContent": {
"_uniqueProp": "086_BP3_nuclear_GCK",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP3",
"ns": "086",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888301",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888301",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--K"
},
{
"entContent": {
"_uniqueProp": "086_PP2_nuclear_GCK",
"additionalComments": "Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores.",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP2",
"ns": "086",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0237",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0049",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0033",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0034",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply to all missense variants in GCK. gnomAD missense constraint score for _GCK_ is 3.07 (observed/expected= 0.5), which is significant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888291",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888291",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--E"
},
{
"entContent": {
"_uniqueProp": "086_PVS1_nuclear_GCK",
"additionalComments": "Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic ",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Use GCK PVS1 decision tree.",
"label": "PVS1",
"ns": "086",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0245",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": " Use _GCK_ PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group[1](#pmid_30096381)\n\n* Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM\\_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD[2](#pmid_24274751). The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding. Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.\n* “Exon skipping or “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” \n * single exon deletions \n * deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 \n * deletions of single **exons 2,3,6 and 7** cause frameshift --> **PVS1** \n * deletions or skipping of **exons 8 and 9** are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> **PVS1** \n * deletions or skipping of **exons 4 and 5** are in-frame and the proportion is \\<10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180[3](#pmid_23957911) according to Beck et al., Biochemistry 2013/ --> **PVS1** \n * deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10 --> **PVS1**\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use _GCK_ PVS1 decision tree.\n\nPer the SVI standard PVS1 decision tree, apply PVS1\\_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use _GCK_ PVS1 decision tree.\n\n* Apply PVS1\\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\\_Supporting + PM2\\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. \n* Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888279",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888279",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--G"
},
{
"entContent": {
"_uniqueProp": "086_PP5_nuclear_GCK",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "086",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888306",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888306",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpi--B"
},
{
"entContent": {
"_uniqueProp": "086_BP1_nuclear_GCK",
"additionalComments": null,
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP1",
"ns": "086",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0205",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888299",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888299",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--G"
},
{
"entContent": {
"_uniqueProp": "086_BS2_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS2",
"ns": "086",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0091",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0224",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "We expect to see hyperglycemia at birth in an individual with \\_GCK\\_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (\\<100 mg/dl / 5.6 mmol/L).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888296",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888296",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--H"
},
{
"entContent": {
"_uniqueProp": "086_BS1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator.",
"label": "BS1",
"ns": "086",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0222",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888295",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888295",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--G"
},
{
"entContent": {
"_uniqueProp": "086_PM4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM4",
"ns": "086",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0233",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0012",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0035",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "009",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "For single amino acid deletions, use as supporting level of evidence.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0059",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "For single amino acid deletions/insertions, use as supporting level of evidence",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888287",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888287",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--H"
},
{
"entContent": {
"_uniqueProp": "086_PM3_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Applicable for variants found in neonatal diabetes. Criterion can also be used to interpret the pathogenicity of a heterozygous variant (i.e., GCK-MODY) if the variant under assessment has also been identified in a patient with neonatal diabetes in the homozygous state or in trans with a P/LP variant or VUS).",
"label": "PM3",
"ns": "086",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0232",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0038",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use SVI-recommended point-based system.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888286",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888286",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpi---"
},
{
"entContent": {
"_uniqueProp": "086_PS4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of the patient must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency considered as exclusionary: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15,16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 16, 17)",
"label": "PS4",
"ns": "086",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0243",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "7 or more occurrences in unrelated individuals = Strong.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "4-6 occurrences in unrelated individuals = Moderate.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888283",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888283",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--K"
},
{
"entContent": {
"_uniqueProp": "086_BP7_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP7",
"ns": "086",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0221",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0219",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \\< 2.0.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888304",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888304",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--M"
},
{
"entContent": {
"_uniqueProp": "086_BP4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP4",
"ns": "086",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0215",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0213",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2[9](#pmid_32123317),[10](#pmid_30661751).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888302",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888302",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--H"
},
{
"entContent": {
"_uniqueProp": "086_BP2_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BP2",
"ns": "086",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0209",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0207",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Also applicable when in cis or trans with a likely pathogenic variant.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888300",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888300",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--J"
},
{
"entContent": {
"_uniqueProp": "086_BS4_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "BS4",
"ns": "086",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0229",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0227",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888298",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888298",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpa--I"
},
{
"entContent": {
"_uniqueProp": "086_PM6_nuclear_GCK",
"additionalComments": "Subsumed in PS2.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM6",
"ns": "086",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888289",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888289",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--J"
},
{
"entContent": {
"_uniqueProp": "086_PM5_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PM5",
"ns": "086",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0234",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0047",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888288",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888288",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--I"
},
{
"entContent": {
"_uniqueProp": "086_PM1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "See attached chart.",
"label": "PM1",
"ns": "086",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0230",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0015",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0028",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "006",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Applicable for glucose- and ATP-binding sites (see attached chart).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0054",
"instructionsToUse": "",
"specificationType": "Gene-specific, Strength",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888284",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888284",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--L"
},
{
"entContent": {
"_uniqueProp": "086_PS3_nuclear_GCK",
"additionalComments": "Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. \nNote that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI), and assays that measure the impact of variants on binding with GKRP and GKA. (Ref 5,6,7,12). For canonical splice site variants, do not use PS3 for RNA studies demonstrating abnormal splicing, since PVS1 will already be used at some level. To use PS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variation the patient has) does not count as PS3.",
"label": "PS3",
"ns": "086",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0242",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "See list of approved functional studies and guidelines for interpretation of data.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "See list of approved functional studies and guidelines for interpretation of data (below).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888282",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888282",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpe--J"
},
{
"entContent": {
"_uniqueProp": "086_PS1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PS1",
"ns": "086",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0240",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0021",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"None"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "No change",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888280",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888280",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxo6--C"
},
{
"entContent": {
"_uniqueProp": "086_BP6_nuclear_GCK",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "086",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888305",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888305",
"modified": "2023-08-11T16:06:03.361Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--F"
},
{
"entContent": {
"_uniqueProp": "086_BA1_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator.",
"label": "BA1",
"ns": "086",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "gnomAD 2.1.1\\* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).\n\n\\*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0201",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0202",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0203",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0089",
"instructionsToUse": "",
"specificationType": [],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888294",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888294",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpi--A"
},
{
"entContent": {
"_uniqueProp": "086_PP3_nuclear_GCK",
"additionalComments": null,
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": null,
"label": "PP3",
"ns": "086",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0238",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0024",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"specificationType": [],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"specificationType": [],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2[9](#pmid_32123317),[10](#pmid_30661751)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888292",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888292",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpK--K"
},
{
"entContent": {
"_uniqueProp": "086_PP1_nuclear_GCK",
"additionalComments": "Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"GCK"
],
"geneType": "nuclear",
"instructionsToUse": "Variable penetrance and phenocopies complicate co-segregation studies. The presence of type 1 and type 2 diabetes phenocopies and significance of variants in unaffected individuals as defined above will need to be considered. We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to classify a family member as unaffected; fasting glucose must be tested and found to be within normal limits (<100 mg/dl = 5.5 mmol/L) or HbA1c test <=5.5% since the GCK range was 5.6 - 7.6% (Ref13).
Presence of clinically significant diabetes complications in anyone with the variant is an exclusion.",
"label": "PP1",
"ns": "086",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"status": {
"Classification Rules In Prep": {
"completed": false
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable for this VCEP",
"id": "0236",
"instructionsToUse": "",
"specificationType": [],
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable for this VCEP",
"id": "0042",
"instructionsToUse": "",
"specificationType": [],
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/32 (5 meioses)\n* \\>1 Family : ≤ 1/16 (4 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/16 (4 meioses)\n* \\>1 Family : ≤ 1/8 (3 meioses)",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Use thresholds suggested by Jarvik and Browning[8](#pmid_27236918)\n\n* Single Family : ≤ 1/8 (3 meioses)\n* \\>1 Family : ≤ ¼ (2 meioses)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1533888290",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1533888290",
"modified": "2023-08-11T16:06:03.360Z",
"modifier": "tonipollin",
"rev": "_h6SHxpC--E"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015967",
"lbl": "monogenic diabetes",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/254"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/8319"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0015967"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_genetic_diabetes_mellitus"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1392102"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C3888631"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C129739"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_1001511"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_183625"
}
],
"definition": {
"val": "Diabetes mellitus that is caused by mutations in a single gene.",
"xrefs": [
"https://doi.org/10.2337/dci20-0065"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "monogenic diabetes",
"xrefs": [
"NCIT:C129739"
]
},
{
"pred": "hasExactSynonym",
"val": "rare genetic diabetes mellitus",
"xrefs": [
"Orphanet:183625"
]
}
],
"xrefs": [
{
"val": "EFO:1001511"
},
{
"val": "MEDGEN:1392102"
},
{
"val": "NCIT:C129739"
},
{
"val": "Orphanet:183625"
},
{
"val": "UMLS:C3888631"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015967",
"name": "monogenic diabetes"
},
"entId": "MONDO:0015967",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015967",
"entType": "Disease",
"ldhId": "467884025",
"ldhIri": "https://genboree.org/cspec/Disease/id/467884025",
"modified": "2025-10-07T15:45:43.374Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xjrq---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056948280787000,
"agr": "HGNC:4195",
"alias_name": [
"hexokinase 4"
],
"alias_symbol": [
"HK4"
],
"ccds_id": [
"CCDS5479",
"CCDS5480"
],
"date_approved_reserved": "1991-06-05",
"date_modified": "2021-05-26",
"date_name_changed": "2016-01-22",
"ena": [
"AF041014"
],
"ensembl_gene_id": "ENSG00000106633",
"entrez_id": "2645",
"enzyme_id": [
"2.7.1.2",
"2.7.1.1"
],
"hgnc_id": "HGNC:4195",
"iuphar": "objectId:2798",
"location": "7p13",
"location_sortable": "07p13",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/GCK",
"LRG_1074|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1074.xml"
],
"mane_select": [
"ENST00000403799.8",
"NM_000162.5"
],
"mgd_id": [
"MGI:1270854"
],
"name": "glucokinase",
"omim_id": [
"138079"
],
"orphanet": 122053,
"prev_name": [
"maturity onset diabetes of the young 2",
"glucokinase (hexokinase 4)"
],
"prev_symbol": [
"MODY2"
],
"pubmed_id": [
1740341,
1502186
],
"refseq_accession": [
"NM_000162"
],
"rgd_id": [
"RGD:2670"
],
"status": "Approved",
"symbol": "GCK",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003tkl.3",
"uniprot_ids": [
"P35557"
],
"uuid": "ea8a5be4-e0f0-4dd4-8d5b-a40844aeb9ff",
"vega_id": "OTTHUMG00000022903"
}
},
"entId": "GCK",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4195",
"entType": "Gene",
"ldhId": "467827496",
"ldhIri": "https://genboree.org/cspec/Gene/id/467827496",
"modified": "2021-10-14T11:36:39.977Z",
"modifier": "genbadmin",
"rev": "_h6SHyr----"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "086_nuclear_GCK",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Semidominant inheritance",
"preferredMondoId": "MONDO:0015967",
"preferredTitle": "monogenic diabetes"
}
],
"gene": "GCK",
"preferredTranscript": "NM_000162.5"
}
],
"ns": "086",
"references": [
{
"auths": [
"DiStefano MT",
"Hemphill SE",
"et al."
],
"doiStr": "10.1016/j.jmoldx.2018.06.005",
"id": "30096381",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 789-801.",
"source": "J Mol Diagn",
"title": "Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants.",
"vol": "20",
"year": "2018"
},
{
"auths": [
"Popp MW",
"Maquat LE"
],
"doiStr": "10.1146/annurev-genet-111212-133424",
"id": "24274751",
"iss": "",
"namespace": "pmid",
"pages": "p. 139-65.",
"source": "Annu Rev Genet",
"title": "Organizing principles of mammalian nonsense-mediated mRNA decay.",
"vol": "47",
"year": "2013"
},
{
"auths": [
"Beck T",
"Miller BG"
],
"doiStr": "10.1021/bi400838t",
"id": "23957911",
"iss": "(36)",
"namespace": "pmid",
"pages": "p. 6232-9.",
"source": "Biochemistry",
"title": "Structural basis for regulation of human glucokinase by glucokinase regulatory protein.",
"vol": "52",
"year": "2013"
},
{
"auths": [
"Brnich SE",
"Abou Tayoun AN",
"et al."
],
"doiStr": "10.1186/s13073-019-0690-2",
"id": "31892348",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 3.",
"source": "Genome Med",
"title": "Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.",
"vol": "12",
"year": "2019"
},
{
"auths": [
"Gloyn AL",
"Odili S",
"et al."
],
"doiStr": "10.1074/jbc.M413146200",
"id": "15677479",
"iss": "(14)",
"namespace": "pmid",
"pages": "p. 14105-13.",
"source": "J Biol Chem",
"title": "Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.",
"vol": "280",
"year": "2005"
},
{
"auths": [
"Beer NL",
"Osbak KK",
"et al."
],
"doiStr": "10.2337/dc11-2420",
"id": "22611063",
"iss": "(7)",
"namespace": "pmid",
"pages": "p. 1482-4.",
"source": "Diabetes Care",
"title": "Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis.",
"vol": "35",
"year": "2012"
},
{
"auths": [
"Raimondo A",
"Chakera AJ",
"et al."
],
"doiStr": "10.1093/hmg/ddu360",
"id": "25015100",
"iss": "(24)",
"namespace": "pmid",
"pages": "p. 6432-40.",
"source": "Hum Mol Genet",
"title": "Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.",
"vol": "23",
"year": "2014"
},
{
"auths": [
"Jarvik GP",
"Browning BL"
],
"doiStr": "10.1016/j.ajhg.2016.04.003",
"id": "27236918",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1077-1081.",
"source": "Am J Hum Genet",
"title": "Consideration of Cosegregation in the Pathogenicity Classification of Genomic Variants.",
"vol": "98",
"year": "2016"
},
{
"auths": [
"Wai HA",
"Lord J",
"et al."
],
"doiStr": "10.1038/s41436-020-0766-9",
"id": "32123317",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. 1005-1014.",
"source": "Genet Med",
"title": "Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.",
"vol": "22",
"year": "2020"
},
{
"auths": [
"Jaganathan K",
"Kyriazopoulou Panagiotopoulou S",
"et al."
],
"doiStr": "10.1016/j.cell.2018.12.015",
"id": "30661751",
"iss": "(3)",
"namespace": "pmid",
"pages": "p. 535-548.e24.",
"source": "Cell",
"title": "Predicting Splicing from Primary Sequence with Deep Learning.",
"vol": "176",
"year": "2019"
},
{
"id": "187f5e4a-1941-5c2d-9c9f-1dc999cc5454",
"namespace": "url",
"value": "https://www.diabetesgenes.org/mody-probability-calculator/"
},
{
"id": "7b8ee3e0-95c7-50ca-a251-415116c1a95b",
"namespace": "footnote",
"value": "Gloyn, et al. (2004). Glucokinase and the Regulation of Blood Sugar In Matschinsky FM & Magnuson MA (Eds), Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. (pp. 92-109). Karger. DOI:10.1159/000079009"
},
{
"auths": [
"Hattersley AT",
"Greeley SAW",
"et al."
],
"doiStr": "10.1111/pedi.12772",
"id": "30225972",
"iss": "",
"namespace": "pmid",
"pages": "p. 47-63.",
"source": "Pediatr Diabetes",
"title": "ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents.",
"vol": "19 Suppl 27",
"year": "2018"
},
{
"auths": [
"Pihoker C",
"Gilliam LK",
"et al."
],
"doiStr": "10.1210/jc.2013-1279",
"id": "23771925",
"iss": "(10)",
"namespace": "pmid",
"pages": "p. 4055-62.",
"source": "J Clin Endocrinol Metab",
"title": "Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.",
"vol": "98",
"year": "2013"
},
{
"auths": [
"McDonald TJ",
"Colclough K",
"et al."
],
"doiStr": "10.1111/j.1464-5491.2011.03287.x",
"id": "21395678",
"iss": "(9)",
"namespace": "pmid",
"pages": "p. 1028-33.",
"source": "Diabet Med",
"title": "Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes.",
"vol": "28",
"year": "2011"
},
{
"auths": [
"Shields BM",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc17-0224",
"id": "28701371",
"iss": "(8)",
"namespace": "pmid",
"pages": "p. 1017-1025.",
"source": "Diabetes Care",
"title": "Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.",
"vol": "40",
"year": "2017"
},
{
"auths": [
"Patel KA",
"Weedon MN",
"et al."
],
"doiStr": "10.2337/dc18-0373",
"id": "30409810",
"iss": "(2)",
"namespace": "pmid",
"pages": "p. e16-e17.",
"source": "Diabetes Care",
"title": "Zinc Transporter 8 Autoantibodies (ZnT8A) and a Type 1 Diabetes Genetic Risk Score Can Exclude Individuals With Type 1 Diabetes From Inappropriate Genetic Testing for Monogenic Diabetes.",
"vol": "42",
"year": "2019"
},
{
"auths": [
"Carlsson A",
"Shepherd M",
"et al."
],
"doiStr": "10.2337/dc19-0747",
"id": "31704690",
"iss": "(1)",
"namespace": "pmid",
"pages": "p. 82-89.",
"source": "Diabetes Care",
"title": "Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study.",
"vol": "43",
"year": "2020"
},
{
"auths": [
"Steele AM",
"Wensley KJ",
"et al."
],
"doiStr": "10.1371/journal.pone.0065326",
"id": "23799006",
"iss": "(6)",
"namespace": "pmid",
"pages": "p. e65326.",
"source": "PLoS One",
"title": "Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies.",
"vol": "8",
"year": "2013"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=2",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": "==1",
"label": "Rule3, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS3_Supporting",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1",
"PS2_Very Strong",
"PM3_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule17, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM1",
"PM3",
"PM4",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PS2_Supporting",
"PS3_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM4_Supporting",
"PM5_Supporting",
"PP1",
"PP2",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1528339124",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528339124",
"modified": "2023-08-11T16:06:03.254Z",
"modifier": "tonipollin",
"rev": "_h6SHyTW--B"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-11-21T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2021-06-04T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2021-08-18T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Monogenic Diabetes",
"shortBaseName": "Diabetes",
"shortTitle": "Monogenic Diabetes VCEP",
"title": "Monogenic Diabetes Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50016",
"entIri": "http://clinicalgenome.org/affiliation/50016",
"entType": "Organization",
"ldhId": "135637640",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637640",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEu--I"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528339111",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528339111",
"modified": "2024-03-05T21:31:26.464Z",
"modifier": "tonipollin",
"rev": "_h6SHykK--K"
},
{
"entContent": {
"description": "",
"namespace": "GN087",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-04T18:05:53.296Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T14:33:57.587Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-06T16:51:27.119Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-08T14:30:32.836Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:31.945Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"087"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN087",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0018997",
"lbl": "Noonan syndrome",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6744"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0018997"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0021060"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10029748"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/18073"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D009634"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/205824006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0028326"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_3490"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34854"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/mondo/sources/icd11foundation/1044395354"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_648"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS163950"
}
],
"definition": {
"val": "Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphism and congenital heart defects.",
"xrefs": [
"Orphanet:648"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#CLINGEN_LABEL",
"val": "Noonan syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan's syndrome",
"xrefs": [
"NCIT:C34854"
]
},
{
"pred": "hasExactSynonym",
"val": "Turner's phenotype, karyotype normal",
"xrefs": [
"DOID:3490"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan-Ehmke syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Ullrich-Noonan syndrome",
"xrefs": [
"GARD:0010955"
]
},
{
"pred": "hasRelatedSynonym",
"val": "pseudo-Ullrich-Turner syndrome",
"xrefs": [
"GARD:0010955"
]
}
],
"xrefs": [
{
"val": "DOID:3490"
},
{
"val": "GARD:10955"
},
{
"val": "ICD9:759.89"
},
{
"val": "MEDGEN:18073"
},
{
"val": "MESH:D009634"
},
{
"val": "MedDRA:10029748"
},
{
"val": "NANDO:1200680"
},
{
"val": "NANDO:2200413"
},
{
"val": "NCIT:C34854"
},
{
"val": "NORD:1513"
},
{
"val": "OMIMPS:163950"
},
{
"val": "Orphanet:648"
},
{
"val": "SCTID:205824006"
},
{
"val": "UMLS:C0028326"
},
{
"val": "icd11.foundation:1044395354"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0018997",
"name": "Noonan syndrome",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0018997",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0018997",
"entType": "Disease",
"ldhId": "135642024",
"ldhIri": "https://genboree.org/cspec/Disease/id/135642024",
"modified": "2024-11-20T17:54:08.081Z",
"modifier": "cspecAdministrator",
"rev": "_iyozwl2---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056954376159200,
"agr": "HGNC:7227",
"alias_symbol": [
"M-RAs",
"R-RAS3",
"RRAS3"
],
"ccds_id": [
"CCDS58855",
"CCDS3100"
],
"date_approved_reserved": "1999-09-29",
"date_modified": "2015-09-03",
"ena": [
"AF022080"
],
"ensembl_gene_id": "ENSG00000158186",
"entrez_id": "22808",
"gene_group": [
"RAS type GTPase family"
],
"gene_group_id": [
389
],
"hgnc_id": "HGNC:7227",
"location": "3q22.3",
"location_sortable": "03q22.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"mane_select": [
"ENST00000423968.7",
"NM_001085049.3"
],
"mgd_id": [
"MGI:1100856"
],
"name": "muscle RAS oncogene homolog",
"omim_id": [
"608435"
],
"pubmed_id": [
9400994,
10446149
],
"refseq_accession": [
"NM_001085049"
],
"rgd_id": [
"RGD:3111"
],
"status": "Approved",
"symbol": "MRAS",
"ucsc_id": "uc003esh.5",
"uniprot_ids": [
"O14807"
],
"uuid": "a58569ba-b5fc-479e-8544-5a9361237b3b",
"vega_id": "OTTHUMG00000159888"
}
},
"entId": "MRAS",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7227",
"entType": "Gene",
"ldhId": "467839815",
"ldhIri": "https://genboree.org/cspec/Gene/id/467839815",
"modified": "2021-10-14T11:36:52.994Z",
"modifier": "genbadmin",
"rev": "_h6SHznu--E"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "087_nuclear_MRAS",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0018997",
"preferredTitle": "Noonan syndrome"
}
],
"gene": "MRAS",
"preferredTranscript": "NM_001085049.3"
}
],
"ns": "087",
"references": []
},
"entType": "RuleSet",
"ldhId": "1528438503",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1528438503",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--C"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1528438490",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1528438490",
"modified": "2023-09-06T21:13:32.160Z",
"modifier": "sharriso",
"rev": "_h6SHykG--U"
},
{
"entContent": {
"description": "RMRP specifications",
"namespace": "GN088",
"releaseNotes": "",
"shortTitle": "Severe Combined Immunodeficiency Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-12T14:52:32.692Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-09-13T17:34:40.911Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-07-20T17:44:14.855Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-10-27T20:45:39.139Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"088"
],
"title": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RMRP Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN088",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0009595",
"lbl": "cartilage-hair hypoplasia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4948"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/6751"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0009595"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/cartilage_hair_hypoplasia"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/6996/cartilage-hair-hypoplasia"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10069596"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/469051294"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/67398"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C535916"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/7720002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0220748"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_14773"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C61245"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_175"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/250250"
}
],
"definition": {
"val": "Cartilage-hair hypoplasia is a disease affecting the bone metaphyses causing small stature from birth.",
"xrefs": [
"Orphanet:175"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "McKusick Type Metaphyseal Chondrodysplasia",
"xrefs": [
"DOID:14773",
"NORD:1414"
]
},
{
"pred": "hasExactSynonym",
"val": "McKusick type metaphyseal chondrodysplasia",
"xrefs": [
"DOID:14773"
]
},
{
"pred": "hasExactSynonym",
"val": "autosomal recessive metaphyseal chondrodysplasia",
"xrefs": [
"Orphanet:175"
]
},
{
"pred": "hasExactSynonym",
"val": "cartilage hair hypoplasia",
"xrefs": [
"NCIT:C61245"
]
},
{
"pred": "hasExactSynonym",
"val": "cartilage-hair hypoplasia",
"xrefs": [
"DOID:14773",
"MONDO:Lexical",
"OMIM:250250",
"Orphanet:175",
"icd11.foundation:469051294"
]
},
{
"pred": "hasExactSynonym",
"val": "metaphyseal chondrodysplasia, McKusick type",
"xrefs": [
"DOID:14773",
"OMIM:250250",
"Orphanet:175"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "CHH",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "cartilage hair hypoplasia like syndrome",
"xrefs": [
"GARD:0006996"
]
},
{
"pred": "hasRelatedSynonym",
"val": "metaphyseal chondrodysplasia McKusick type",
"xrefs": [
"GARD:0006996"
]
},
{
"pred": "hasRelatedSynonym",
"val": "metaphyseal chondrodysplasia, Mckusick type"
}
],
"xrefs": [
{
"val": "DOID:14773"
},
{
"val": "GARD:6996"
},
{
"val": "MEDGEN:67398"
},
{
"val": "MESH:C535916"
},
{
"val": "MedDRA:10069596"
},
{
"val": "NCIT:C61245"
},
{
"val": "NORD:1414"
},
{
"val": "OMIM:250250"
},
{
"val": "Orphanet:175"
},
{
"val": "SCTID:7720002"
},
{
"val": "UMLS:C0220748"
},
{
"val": "icd11.foundation:469051294"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0009595",
"name": "cartilage-hair hypoplasia"
},
"entId": "MONDO:0009595",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0009595",
"entType": "Disease",
"ldhId": "467873086",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873086",
"modified": "2025-10-07T15:43:57.702Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7V8mK---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056959344312300,
"agr": "HGNC:10031",
"alias_symbol": [
"RMRPR",
"RRP2",
"NME1"
],
"date_approved_reserved": "1989-06-30",
"date_modified": "2021-04-13",
"date_name_changed": "2002-05-23",
"ena": [
"M29916"
],
"ensembl_gene_id": "ENSG00000277027",
"entrez_id": "6023",
"hgnc_id": "HGNC:10031",
"location": "9p13.3",
"location_sortable": "09p13.3",
"locus_group": "non-coding RNA",
"locus_type": "RNA, misc",
"lsdb": [
"LRG_163|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_163.xml"
],
"mgd_id": [
"MGI:97937"
],
"name": "RNA component of mitochondrial RNA processing endoribonuclease",
"omim_id": [
"157660"
],
"orphanet": 138742,
"prev_name": [
"cartilage-hair hypoplasia"
],
"prev_symbol": [
"CHH"
],
"pubmed_id": [
11207361,
1623519
],
"refseq_accession": [
"NR_003051"
],
"rna_central_id": [
"URS000075C8FA"
],
"status": "Approved",
"symbol": "RMRP",
"ucsc_id": "uc003zxh.2",
"uuid": "92d563e0-2660-43de-b4f9-fc8fe3ecdbab"
}
},
"entId": "RMRP",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10031",
"entType": "Gene",
"ldhId": "467848363",
"ldhIri": "https://genboree.org/cspec/Gene/id/467848363",
"modified": "2021-10-14T11:37:01.205Z",
"modifier": "genbadmin",
"rev": "_h6SHz8C--_"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "088_nuclear_RMRP",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0009595",
"preferredTitle": "cartilage-hair hypoplasia"
}
],
"gene": "RMRP",
"preferredTranscript": "NR_003051.3"
}
],
"ns": "088",
"references": []
},
"entType": "RuleSet",
"ldhId": "1529230108",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1529230108",
"modified": "2023-06-08T21:01:53.947Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--D"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "SCID",
"approval": {
"step1": {
"approvalDate": "2021-01-28T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-03-30T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-07-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-10-02T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Severe Combined Immunodeficiency Disease ",
"shortBaseName": "SCID",
"shortTitle": "Severe Combined Immunodeficiency Disease VCEP",
"title": "Severe Combined Immunodeficiency Disease Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50091",
"entIri": "http://clinicalgenome.org/affiliation/50091",
"entType": "Organization",
"ldhId": "639508898",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508898",
"modified": "2023-10-03T23:07:05.645Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--i"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1529230095",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529230095",
"modified": "2023-10-27T20:45:39.390Z",
"modifier": "strande@email.unc.edu",
"rev": "_h6SHykG--_"
},
{
"entContent": {
"approvedOn": "2023-11-24T13:46:56.766Z",
"description": "The following criteria are for classic or attenuated familial adenomatous polyposis only and does not apply to Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, MONDO:0017790).\nThe preferred transcript for coding, intronic and promoter 1A variants is NM_000038.6 (MANE transcript). The NM_001127510.2 transcript differs from NM_000038.6 in the number of \"non-coding\" exons in the 5' region, which results in different exon numbering (in NM_000038.6 there is only one non-coding exon, in NM_001127510.2 there is one additional non-coding exon and one non-coding exon overlapping with NM_000038.6; the 15 coding exons are the same). For the promoter 1B deletion the preferred transcript is NM_001127511.3, which has an alternative coding exon 1. The LRG_130 summarizes all three “additional” exons of the previously mentioned transcripts, resulting in 18 exons). To standardize, variants in this document are described in HGVS nomenclature according to their positions in the NM_000038.6 transcript unless otherwise specified. Numbered exons in this document refers to exons 1-16 in the NM_000038.6transcript. Refer to Supplementary Table 1 for exon number conversions. \nIt is important to note that these criteria are not developed for low/moderate penetrant variants (e. g. c.3920T>A p.(Ile1307Lys) and c.3949G>C p.(Glu1317Gln)).",
"namespace": "GN089",
"releaseNotes": "* Correction of some inaccuracies in the Rules for Combining Criteria.\n* Addition of some relevant instructions out of the supplementary material\n* Change in Fig. 1A: Update of the possible pathways for “G to non-G changes”\n* Change in Fig. 1B: Transfer of splice variants c.136-1G>A,C,T; c.136-2A>C,G,T; c.220+1G>A,C,T and c.220+2T>A,C,G from List E to List A and transfer of c.220G>A,C,T from List E to List B based on RNA and phenotype data\n* Update of the supplementary material file.",
"releasedUnderRevision": true,
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "xiaoyuyin",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-13T04:32:42.802Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-10-20T13:21:03.456Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-20T13:04:16.330Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-11-21T20:45:32.523Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "ispier",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-11-24T13:46:56.766Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-09-14T10:53:29.300Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-17T17:10:15.332Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "ispier",
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-10-20T13:04:16.330Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"089"
],
"title": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0",
"version": "2.1.0",
"versioned": true
},
"entId": "GN089",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "089_BP6_nuclear_APC",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "089",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527159",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527159",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--I"
},
{
"entContent": {
"_uniqueProp": "089_PS2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "089",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0016",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 4 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Applicable",
"id": "0051",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "004",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1-1.5 _de novo_ score. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527157",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527157",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--C"
},
{
"entContent": {
"_uniqueProp": "089_BS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)",
"label": "BS1",
"ns": "089",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.001%** (0.00001).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0086",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527152",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527152",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--_"
},
{
"entContent": {
"_uniqueProp": "089_BA1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)",
"label": "BA1",
"ns": "089",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "GnomAD Popmax Filtering Allele Frequency (AF) **≥ 0.1%** (0.001).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527147",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527147",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6---"
},
{
"entContent": {
"_uniqueProp": "089_BS3_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BS3",
"ns": "089",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration\n\n**AND**\n\nbiallelic expression is shown and/or nonsense-mediated decay inhibition was used.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition\n\n**OR**\n\n**Protein assay** show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_, see PMID: 33348689)",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527138",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527138",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--x"
},
{
"entContent": {
"_uniqueProp": "089_BP7_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "The use of BP7 with BP4 is allowed.\n\nRecommended splice prediction programs: see PS1",
"label": "BP7",
"ns": "089",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0065",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527149",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527149",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--G"
},
{
"entContent": {
"_uniqueProp": "089_BS2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.",
"label": "BS2",
"ns": "089",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "≥ 10 points for healthy individuals **OR** ≥ 2 times in homozygous state.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years \n\\+ Less than 5 adenomatous polyps in a colonoscopy \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0098",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "≥ 3 points for healthy individuals.\n\nA **healthy individual** worth 1 point is defined by:\n\nAge ≥ 50 years \n\\+ Less than 5 adenomatous polyps in a colonoscopy \n\\+ Absence of features in Table 1\n\n**OR**\n\nAge ≥ 50 years \n\\+ Colorectal cancer/polyposis was not the indication for testing\n\nA **healthy individual** worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527142",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527142",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--A"
},
{
"entContent": {
"_uniqueProp": "089_BP2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "089",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0084",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Observed _in trans_ with a (Likely) Pathogenic _APC_ variant **OR** ≥ 3 times in an unknown phase with different (Likely) Pathogenic _APC_ variants.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527136",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527136",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--_"
},
{
"entContent": {
"_uniqueProp": "089_PP3_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "Recommended splice prediction programs: see PS1",
"label": "PP3",
"ns": "089",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Approved For Release": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects.\n\n**Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527150",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527150",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpC--P"
},
{
"entContent": {
"_uniqueProp": "089_PM6_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "PM6_VeryStrong: ≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. ",
"label": "PM6",
"ns": "089",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0037",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0010",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "1-1.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0022",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "0.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1** and **2**.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527148",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527148",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--F"
},
{
"entContent": {
"_uniqueProp": "089_PP2_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "089",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527141",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527141",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--y"
},
{
"entContent": {
"_uniqueProp": "089_BP1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "A number of assumed “missense” variants are in fact splice variants. At least several splice prediction tools should be used.\n\nRecommended splice prediction programs: see PS1",
"label": "BP1",
"ns": "089",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0075",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0082",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527140",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527140",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--D"
},
{
"entContent": {
"_uniqueProp": "089_PM5_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM5",
"ns": "089",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0056",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The reported missense variant was determined to be Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications.\n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5\\_supporting. No missense variant has been classified as Pathogenic based on current evidence. \n\nGrantham´s distance of the variant under assessment must have an equal or higher score than the reported variant \\[Reference 3\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527137",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527137",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--C"
},
{
"entContent": {
"_uniqueProp": "089_PS4_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS4",
"ns": "089",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0029",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "≥ 16 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "4-15.5 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0057",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "2-3.5 phenotype points. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0032",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "1-1.5 phenotype point. For phenotype points curation see **Table 1**.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527135",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527135",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpC--N"
},
{
"entContent": {
"_uniqueProp": "089_PM2_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "General recommendation: Use the total population from the non-cancer dataset from gnomAD (v2.1.1)",
"label": "PM2",
"ns": "089",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Approved For Release": {
"completed": true
},
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency \\< 0.001% (0.00001) if the allele count is ≤ 1.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527134",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527134",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpC--M"
},
{
"entContent": {
"_uniqueProp": "089_PS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "Recommended splice prediction programs:\n\n* SpliceAI: https://spliceailookup.broadinstitute.org/,\n* MaxEntScan : http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html for 5’splice sites and http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq_acc.html for 3’splice sites \n* VarSeak: [https://varseak.bio/](https://varseak.bio/)\n\nFor SpliceAI a loss of the native splice site is considered for scores between 0.8 and 1. A gain of a cryptic splice site is considered strong for scores between 0.8 and 1 and as moderate for a score between 0.2 and 0.8. \n\nFor MaxEntScan predictions a score of >3 is required for credibility of a native site prediction and a threshold of -15% is considered for native splice site loss (Houdayer et al. 2012, PMID 22505045). A score >3 is used as a conservative measure for cryptic site use in the context of native site loss.",
"label": "PS1",
"ns": "089",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The previously established variant was classified as Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications.\n\nThis criterion can be applied to both missense and splice variants in _APC_. \n\n**Missense variants:** when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). \n\nThere are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. \n\n**Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0036",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527158",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527158",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--H"
},
{
"entContent": {
"_uniqueProp": "089_BP5_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "(Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous variants in _POLD1_ or _POLE_; biallelic variants in _MUTYH, NTHL1_ or _MSH3_; in patients with onset in childhood / adolescence: biallelic variants in _MLH1, MSH2, MSH6_ or _PMS2_). This rule is only applicable when a colorectal polyposis phenotype is present.",
"label": "BP5",
"ns": "089",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0073",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0217",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"No change"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527153",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527153",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--2"
},
{
"entContent": {
"_uniqueProp": "089_PM3_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM3",
"ns": "089",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0058",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Not applicable",
"id": "007",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0027",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527144",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527144",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--B"
},
{
"entContent": {
"_uniqueProp": "089_PP5_nuclear_APC",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "089",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527143",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527143",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--E"
},
{
"entContent": {
"_uniqueProp": "089_BP4_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "Recommended splice prediction programs: see PS1",
"label": "BP4",
"ns": "089",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "**Missense variants:** BP4 is not applicable.\n\n**Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527160",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527160",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpa--J"
},
{
"entContent": {
"_uniqueProp": "089_PP4_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PP4",
"ns": "089",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "005",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0018",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0063",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527156",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527156",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpC--Q"
},
{
"entContent": {
"_uniqueProp": "089_BP3_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "089",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527155",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527155",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--B"
},
{
"entContent": {
"_uniqueProp": "089_PP1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"instructionsToUse": "Affected individuals exhibit at least 0.5 point of the phenotype point system (see Table 1), for relatives also ≥ 10 or “multiple” colorectal adenomas are considered as 0.5 point.\n\nOnly genotype and phenotype positive individuals and obligate carriers with phenotype are counted (note: carriers who have received chemoprevention and may have a milder phenotype can also be counted).",
"label": "PP1",
"ns": "089",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Variant segregates in ≥ 7 meioses in ≥ 2 families.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Variant segregates in 5-6 meioses in ≥ 1 family.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Variant segregates in 3-4 meioses in ≥ 1 family.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527154",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527154",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxp6--A"
},
{
"entContent": {
"_uniqueProp": "089_PS3_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PS3",
"ns": "089",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "**RNA assays** show\n\n1. a premature stop codon \n OR\n2. inframe skipping of exon 13 or 14\n\n**AND** the absence of full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "**RNA assays** show\n\n1. a premature stop codon \n **OR**\n2. inframe skipping of exon 13 or 14\n\n**AND** \\< 10% of full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0039",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "**RNA assays** show \n\n1. a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n3. other inframe skipping AND absent or \\< 10% full-length transcript.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0045",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "**RNA assays** show \n\n1. inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides \n **OR**\n2. over-expression of an alternative transcript (exons 10, 11 or 15)\n\n**Protein assays** show\n\nIncreased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_) \\[Reference 2\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527151",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527151",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--1"
},
{
"entContent": {
"_uniqueProp": "089_PVS1_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PVS1",
"ns": "089",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \\[Reference 1\\].",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527146",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527146",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--0"
},
{
"entContent": {
"_uniqueProp": "089_PM1_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "089",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527145",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527145",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--z"
},
{
"entContent": {
"_uniqueProp": "089_BS4_nuclear_APC",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "BS4",
"ns": "089",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see **Table 1**).",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0228",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Affected member without the variant must score at least 0.5 phenotype points (see **Table 1**).",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527139",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527139",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpC--O"
},
{
"entContent": {
"_uniqueProp": "089_PM4_nuclear_APC",
"additionalComments": "",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"APC"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "089",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1553527133",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1553527133",
"modified": "2023-11-24T13:46:57.486Z",
"modifier": "ispier",
"rev": "_h6SHxpe--w"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0021056",
"lbl": "familial adenomatous polyposis 1",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/398651"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2713442"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0080409"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/175100"
}
],
"definition": {
"val": "An autosomal dominant disorder caused by pathogenic variants in the APC gene, characterized by the development of colorectal adenomatous polyposis, a very high risk of colorectal cancer and other extracolonic manifestations including both classic and attenuated familial adenomatous polyposis (FAP).",
"xrefs": [
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasBroadSynonym",
"val": "adenomatous polyposis coli"
},
{
"pred": "hasExactSynonym",
"val": "APC-related adenomatous polyposis",
"xrefs": [
"https://www.clinicalgenome.org/working-groups/clinical-domain/hereditary-cancer/"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "FAP1",
"xrefs": [
"OMIM:175100"
]
},
{
"pred": "hasExactSynonym",
"val": "adenoma, periampullary, somatic"
},
{
"pred": "hasExactSynonym",
"val": "familial adenomatous polyposis 1",
"xrefs": [
"DOID:0080409",
"MONDO:Lexical",
"OMIM:175100"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Gardner syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "adenomatous polyposis coli, attenuated"
},
{
"pred": "hasRelatedSynonym",
"val": "adenomatous polyposis of the colon"
},
{
"pred": "hasRelatedSynonym",
"val": "brain tumor-polyposis syndrome 2"
},
{
"pred": "hasRelatedSynonym",
"val": "familial adenomatous polyposis, attenuated"
},
{
"pred": "hasRelatedSynonym",
"val": "familial polyposis of the colon"
},
{
"pred": "hasRelatedSynonym",
"val": "polyposis, adenomatous intestinal"
}
],
"xrefs": [
{
"val": "DOID:0080409"
},
{
"val": "MEDGEN:398651"
},
{
"val": "OMIM:175100"
},
{
"val": "UMLS:C2713442"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0021056",
"name": "familial adenomatous polyposis 1"
},
"entId": "MONDO:0021056",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0021056",
"entType": "Disease",
"ldhId": "467886956",
"ldhIri": "https://genboree.org/cspec/Disease/id/467886956",
"modified": "2025-10-07T15:47:11.899Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Y6_u---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056942534590500,
"agr": "HGNC:583",
"alias_name": [
"protein phosphatase 1, regulatory subunit 46"
],
"alias_symbol": [
"DP2",
"DP3",
"DP2.5",
"PPP1R46"
],
"ccds_id": [
"CCDS4107"
],
"cosmic": "APC",
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-25",
"ena": [
"M74088"
],
"ensembl_gene_id": "ENSG00000134982",
"entrez_id": "324",
"gene_group": [
"Armadillo repeat containing",
"Protein phosphatase 1 regulatory subunits"
],
"gene_group_id": [
409,
694
],
"hgnc_id": "HGNC:583",
"location": "5q22.2",
"location_sortable": "05q22.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Adenomatous polyposis coli mutation database|http://p53.free.fr/",
"UMD Locus Specific Databases|http://www.umd.be/",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/APC",
"APC database at LOVD-China|http://genomed.org/LOVD/HNPCC/home.php?select_db=APC",
"LOVD - Leiden Open Variation Database|http://proteomics.bio21.unimelb.edu.au/lovd/genes/APC",
"LRG_130|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_130.xml"
],
"mane_select": [
"ENST00000257430.9",
"NM_000038.6"
],
"mgd_id": [
"MGI:88039"
],
"name": "APC regulator of WNT signaling pathway",
"omim_id": [
"611731"
],
"orphanet": 123393,
"prev_name": [
"adenomatosis polyposis coli",
"adenomatous polyposis coli",
"APC, WNT signaling pathway regulator"
],
"pubmed_id": [
1651563
],
"refseq_accession": [
"NM_000038"
],
"rgd_id": [
"RGD:2123"
],
"status": "Approved",
"symbol": "APC",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003kpy.5",
"uniprot_ids": [
"P25054"
],
"uuid": "450194a3-a136-4564-9528-d08ae834fc62",
"vega_id": "OTTHUMG00000128806"
}
},
"entId": "APC",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:583",
"entType": "Gene",
"ldhId": "467817382",
"ldhIri": "https://genboree.org/cspec/Gene/id/467817382",
"modified": "2021-10-14T11:36:29.534Z",
"modifier": "genbadmin",
"rev": "_h6SHyCe--L"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "089_nuclear_APC",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": " Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0021056",
"preferredTitle": "familial adenomatous polyposis 1"
}
],
"gene": "APC",
"preferredTranscript": "NM_000038.6"
}
],
"ns": "089",
"references": [
{
"auths": [
"Abou Tayoun AN",
"Pesaran T",
"et al."
],
"doiStr": "10.1002/humu.23626",
"id": "30192042",
"iss": "(11)",
"namespace": "pmid",
"pages": "p. 1517-1524.",
"source": "Hum Mutat",
"title": "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion.",
"vol": "39",
"year": "2018"
},
{
"auths": [
"Juanes MA"
],
"doiStr": "10.3390/cancers12123811",
"id": "33348689",
"iss": "(12)",
"namespace": "pmid",
"pages": "",
"source": "Cancers (Basel)",
"title": "Cytoskeletal Control and Wnt Signaling-APC's Dual Contributions in Stem Cell Division and Colorectal Cancer.",
"vol": "12",
"year": "2020"
},
{
"auths": [
"Grantham R"
],
"doiStr": "10.1126/science.185.4154.862",
"id": "4843792",
"iss": "(4154)",
"namespace": "pmid",
"pages": "p. 862-4.",
"source": "Science",
"title": "Amino acid difference formula to help explain protein evolution.",
"vol": "185",
"year": "1974"
}
],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=2",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"label": "Rule11, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": "==1",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==2",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Supporting",
"BS3_Supporting",
"BS4_Supporting",
"BP1",
"BP2",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS2",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule18, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS2",
"PS3",
"PS4",
"PM6_Strong",
"PP1_Strong"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule21, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PS2_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule22"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule23, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule23, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule23, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule23"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule24, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule24"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule25, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule25, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule25"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule26, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule26"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule26, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule26"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PS2_Very Strong",
"PS3_Very Strong",
"PS4_Very Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule24"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PS2_Moderate",
"PS3_Moderate",
"PS4_Moderate",
"PM5",
"PM6",
"PP1_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule25, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS3_Supporting",
"PS4_Supporting",
"PM2_Supporting",
"PM5_Supporting",
"PM6_Supporting",
"PP1",
"PP3"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule25, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule25"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule26, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule26"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1529292804",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1529292804",
"modified": "2023-11-24T13:46:57.386Z",
"modifier": "ispier",
"rev": "_h6SHyTK--B"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "CRC",
"approval": {
"step1": {
"approvalDate": "2021-02-12T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2022-05-04T00:00:00.000Z",
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2022-12-05T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "InSiGHT Hereditary Colorectal Cancer/Polyposis",
"shortBaseName": "CRC",
"shortTitle": "InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP",
"title": "InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50099",
"entIri": "http://clinicalgenome.org/affiliation/50099",
"entType": "Organization",
"ldhId": "639508901",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508901",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--c"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1529292791",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529292791",
"modified": "2023-11-24T13:46:57.319Z",
"modifier": "ispier",
"rev": "_h6SHykS--S"
},
{
"entContent": {
"description": "VWD type 2N rule specifications",
"namespace": "GN090",
"releaseNotes": "",
"shortTitle": "von Willebrand Disease Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-13T21:04:07.328Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2022-12-13T13:31:56.852Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2022-12-09T20:56:32.630Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-01-06T15:51:23.401Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-02-29T16:02:53.417Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-withdrawn",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-15T19:23:59.886Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T23:04:00.855Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"090"
],
"title": "ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN090",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0015631",
"lbl": "von Willebrand disease type 2N",
"meta": {
"basicPropertyValues": [
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1091176565"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/266187"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/359732009"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1282975"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C131689"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_166093"
}
],
"definition": {
"val": "Type 2N von Willebrand disease (type 2N VWD) is a subtype of type 2 VWD characterized by a bleeding disorder associated with a marked decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for factor VIII (FVIII).",
"xrefs": [
"Orphanet:166093"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_subtype_of_a_disorder",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease Normandy variant",
"xrefs": [
"NCIT:C131689"
]
},
{
"pred": "hasExactSynonym",
"val": "von Willebrand disease, type 2N",
"xrefs": [
"NCIT:C131689"
]
}
],
"xrefs": [
{
"val": "GARD:17024"
},
{
"val": "MEDGEN:266187"
},
{
"val": "NCIT:C131689"
},
{
"val": "Orphanet:166093"
},
{
"val": "SCTID:359732009"
},
{
"val": "UMLS:C1282975"
},
{
"val": "icd11.foundation:1091176565"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0015631",
"name": "von Willebrand disease type 2N"
},
"entId": "MONDO:0015631",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0015631",
"entType": "Disease",
"ldhId": "467885573",
"ldhIri": "https://genboree.org/cspec/Disease/id/467885573",
"modified": "2025-10-07T15:45:38.322Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Xen6---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056967233798100,
"agr": "HGNC:12726",
"ccds_id": [
"CCDS8539"
],
"date_approved_reserved": "1986-01-01",
"date_modified": "2021-05-26",
"ensembl_gene_id": "ENSG00000110799",
"entrez_id": "7450",
"gene_group": [
"Receptor ligands"
],
"gene_group_id": [
542
],
"hgnc_id": "HGNC:12726",
"iuphar": "ligandId:6755",
"location": "12p13.31",
"location_sortable": "12p13.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Von Willebrand Factor Database|http://vwf.group.shef.ac.uk/",
"LRG_587|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_587.xml"
],
"mane_select": [
"ENST00000261405.10",
"NM_000552.5"
],
"mgd_id": [
"MGI:98941"
],
"name": "von Willebrand factor",
"omim_id": [
"613160"
],
"orphanet": 120487,
"prev_symbol": [
"F8VWF"
],
"pubmed_id": [
2251280
],
"refseq_accession": [
"NM_000552"
],
"rgd_id": [
"RGD:621759"
],
"status": "Approved",
"symbol": "VWF",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001qnn.2",
"uniprot_ids": [
"P04275"
],
"uuid": "d06e9de2-4d03-4710-8a4f-542fcb6e4074",
"vega_id": "OTTHUMG00000168265"
}
},
"entId": "VWF",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12726",
"entType": "Gene",
"ldhId": "467863817",
"ldhIri": "https://genboree.org/cspec/Gene/id/467863817",
"modified": "2021-10-14T11:37:15.362Z",
"modifier": "genbadmin",
"rev": "_h6SH0P---A"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "090_nuclear_VWF",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0015631",
"preferredTitle": "von Willebrand disease type 2N"
}
],
"gene": "VWF",
"preferredTranscript": "NM_000552.5"
}
],
"ns": "090",
"references": []
},
"entType": "RuleSet",
"ldhId": "1529372875",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1529372875",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTS--L"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "VWD",
"approval": {
"step1": {
"approvalDate": "2019-12-02T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2023-01-06T15:51:24.825Z",
"approved": true
},
"step3": {
"approvalDate": "2024-06-07T16:33:27.420Z",
"approved": true
},
"step4": {
"approvalDate": "2024-06-24T16:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "von Willebrand Disease ",
"shortBaseName": "VWD",
"shortTitle": "von Willebrand Disease VCEP",
"title": "von Willebrand Disease Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50051",
"entIri": "http://clinicalgenome.org/affiliation/50051",
"entType": "Organization",
"ldhId": "639508886",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508886",
"modified": "2024-07-08T12:29:32.500Z",
"modifier": "cspecAdministrator",
"rev": "_iHHQEcW---"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1529372862",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529372862",
"modified": "2024-02-29T16:02:53.580Z",
"modifier": "leekristy",
"rev": "_h6SHykK--H"
},
{
"entContent": {
"description": "",
"namespace": "GN091",
"releaseNotes": "",
"shortTitle": "Lysosomal Storage Disorders Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-17T15:07:17.321Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-19T12:29:38.431Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-31T16:50:23.475Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-06-28T20:02:05.227Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-12-14T22:51:01.515Z"
},
"name": "Pilot Rules Submitted"
}
],
"tagNameSpaces": [
"091"
],
"title": "ClinGen Lysosomal Storage Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN091",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0001586",
"lbl": "mucopolysaccharidosis type 1",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0001586"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/scheie_syndrome"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0020186"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10056886"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1539226250"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/44171"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/75610003"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0023786"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12802"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C85053"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_579"
}
],
"definition": {
"val": "The most common type of mucopolysaccharidosis. It is inherited in an autosomal recessive pattern. It comprises a group of lysosomal storage diseases which includes the most severe form (Hurler syndrome) and the mildest form (Scheie syndrome).",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Alpha-L-iduronidase deficiency",
"xrefs": [
"Orphanet:579",
"icd11.foundation:1539226250"
]
},
{
"pred": "hasExactSynonym",
"val": "MPS I - Hurler syndrome",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MPS1",
"xrefs": [
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "MPSI",
"xrefs": [
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"val": "Mucopolysaccharidosis Type I",
"xrefs": [
"NCIT:C85053",
"NORD:1462",
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"val": "iduronidase deficiency disease",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasExactSynonym",
"val": "lipochondrodystrophy",
"xrefs": [
"DOID:12802",
"icd11.foundation:1539226250"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis type 1",
"xrefs": [
"MONDO:0018934",
"Orphanet:579",
"icd11.foundation:1539226250"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis type I",
"xrefs": [
"MONDORULE:1",
"NCIT:C85053",
"Orphanet:579"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis, MPS-I",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasExactSynonym",
"val": "mucopolysaccharidosis, type 1",
"xrefs": [
"DOID:12802"
]
},
{
"pred": "hasNarrowSynonym",
"val": "Hurler syndrome"
},
{
"pred": "hasRelatedSynonym",
"val": "Hurler syndrome (subtype)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Hurler-Scheie syndrome (subtype)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "IDUA deficiency",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "MPS 1",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "MPS I",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Scheie syndrome (subtype) formerly known as Mucopoly-saccharidosis type V)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "attenuated MPS I (subtype, includes Hurler-Scheie and Scheie syndrome)",
"xrefs": [
"GARD:0010335"
]
},
{
"pred": "hasRelatedSynonym",
"val": "mucopolysaccharidosis I"
},
{
"pred": "hasRelatedSynonym",
"val": "severe MPS I (subtype, also known as Hurler syndrome)",
"xrefs": [
"GARD:0010335"
]
}
],
"xrefs": [
{
"val": "DOID:12802"
},
{
"val": "GARD:10335"
},
{
"val": "MEDGEN:44171"
},
{
"val": "MedDRA:10056886"
},
{
"val": "NANDO:2200547"
},
{
"val": "NANDO:2201168"
},
{
"val": "NCIT:C85053"
},
{
"val": "NORD:1462"
},
{
"val": "Orphanet:579"
},
{
"val": "SCTID:75610003"
},
{
"val": "UMLS:C0023786"
},
{
"val": "icd11.foundation:1539226250"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0001586",
"name": "mucopolysaccharidosis type 1"
},
"entId": "MONDO:0001586",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0001586",
"entType": "Disease",
"ldhId": "467883532",
"ldhIri": "https://genboree.org/cspec/Disease/id/467883532",
"modified": "2025-10-07T15:42:07.827Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7URPa---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056949806465000,
"agr": "HGNC:5391",
"alias_name": [
"mucopolysaccharidosis type I"
],
"alias_symbol": [
"MPS1",
"MPSI"
],
"ccds_id": [
"CCDS87198",
"CCDS3343"
],
"date_approved_reserved": "2001-06-22",
"date_modified": "2021-05-26",
"date_name_changed": "2019-08-12",
"ena": [
"M74715"
],
"ensembl_gene_id": "ENSG00000127415",
"entrez_id": "3425",
"enzyme_id": [
"3.2.1.76"
],
"gene_group": [
"Glycoside hydrolases"
],
"gene_group_id": [
1650
],
"hgnc_id": "HGNC:5391",
"location": "4p16.3",
"location_sortable": "04p16.3",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_1277|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_1277.xml"
],
"mane_select": [
"ENST00000514224.2",
"NM_000203.5"
],
"mgd_id": [
"MGI:96418"
],
"name": "alpha-L-iduronidase",
"omim_id": [
"252800"
],
"orphanet": 122572,
"prev_name": [
"iduronidase, alpha-L-"
],
"pubmed_id": [
1832239
],
"refseq_accession": [
"NM_000203"
],
"rgd_id": [
"RGD:1310943"
],
"status": "Approved",
"symbol": "IDUA",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc003gby.5",
"uniprot_ids": [
"P35475"
],
"uuid": "6eda0e13-ca99-48f3-9857-ebba3b419fec",
"vega_id": "OTTHUMG00000088901"
}
},
"entId": "IDUA",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5391",
"entType": "Gene",
"ldhId": "467830262",
"ldhIri": "https://genboree.org/cspec/Gene/id/467830262",
"modified": "2021-10-14T11:36:42.752Z",
"modifier": "genbadmin",
"rev": "_h6SHz-2--T"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "091_nuclear_IDUA",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0001586",
"preferredTitle": "mucopolysaccharidosis type 1"
}
],
"gene": "IDUA",
"preferredTranscript": "NM_000203.4"
}
],
"ns": "091",
"references": []
},
"entType": "RuleSet",
"ldhId": "1529725542",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1529725542",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--E"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approvalDate": "2018-02-21T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2018-09-17T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2019-08-21T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2019-08-21T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Lysosomal Diseases",
"shortBaseName": "LSD",
"shortTitle": "Lysosomal Diseases VCEP",
"title": "Lysosomal Diseases Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50009",
"entIri": "http://clinicalgenome.org/affiliation/50009",
"entType": "Organization",
"ldhId": "135637633",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637633",
"modified": "2023-04-27T19:13:01.752Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEC--b"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1529725529",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1529725529",
"modified": "2023-12-14T22:51:01.740Z",
"modifier": "jennifer.goldstein@unc.edu",
"rev": "_h6SHykG--c"
},
{
"entContent": {
"approvedOn": "2023-12-21T20:16:32.552Z",
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA1 and BRCA2",
"namespace": "GN092",
"releaseNotes": "Updates in v1.1: \nUpdated web-link for suggested co-segregation analysis tool (COOL) \nUpdated assigned PVS1 codes for some variants in Specifications Table 4 \nUpdated assigned PS3/BS3 codes for some variants in Specifications Table 9, including results updates from interim Findlay report \nCorrected typos and errors \nAdded Supplementary table 16 - mRNA assay evidence used to highlight IVS1/2 variants eligible for PVS1 (RNA) code \nClarified code combinations table in Specifications document: any conflicting pathogenic and benign evidence codes should be resolved using approach 2 (points system)",
"releasedUnderRevision": true,
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "mandyS",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-21T03:29:02.227Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-23T06:06:30.683Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-10T20:52:53.136Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T17:33:36.969Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-12-21T20:16:32.552Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-23T05:45:36.743Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"092"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN092",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "092_BP6_nuclear_BRCA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "092",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165320",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165320",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--L"
},
{
"entContent": {
"_uniqueProp": "092_PS3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9**, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "PS3",
"ns": "092",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165312",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165312",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--K"
},
{
"entContent": {
"_uniqueProp": "092_PVS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5\\_PTC code (See Appendix D for details).\n\n**See Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the** _**BRCA1**_ **and** _**BRCA2**_ **PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor +/- 1,2)) – organized by exon.** See Appendix Figure 3,4 and Table 5 for further justification.\n\nSee **Specifications** **Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.",
"label": "PVS1",
"ns": "092",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165307",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165307",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--F"
},
{
"entContent": {
"_uniqueProp": "092_PM1_nuclear_BRCA1",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "092",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165306",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165306",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---A"
},
{
"entContent": {
"_uniqueProp": "092_PM3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nVariant under assessment must be sufficiently rare (meet PM2\\_Supporting, or PM2 not applicable).\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nFor related individuals score only most severe presentation.\n\nAlso see **Specifications Table 6** for additional stipulations",
"label": "PM3",
"ns": "092",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165305",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165305",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---F"
},
{
"entContent": {
"_uniqueProp": "092_BS2_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nSee **Specifications Table 8** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\n\nAlso see **Specifications Table 8** for additional stipulations.",
"label": "BS2",
"ns": "092",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165303",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165303",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---E"
},
{
"entContent": {
"_uniqueProp": "092_BP2_nuclear_BRCA1",
"additionalComments": "Applied only in the context of BS2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "092",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165297",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165297",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--D"
},
{
"entContent": {
"_uniqueProp": "092_PM2_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth \\<25 at region around the variant.",
"label": "PM2",
"ns": "092",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165295",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165295",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---B"
},
{
"entContent": {
"_uniqueProp": "092_PP4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nSee Specifications Table7 for example application.",
"label": "PP4",
"ns": "092",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR>18.7:1\n\nPP4\\_Very Strong – LR>350:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR>4.3:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR >2.08:1 \n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165317",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165317",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--L"
},
{
"entContent": {
"_uniqueProp": "092_PP1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tool COOL located on this website:[http://bjfenglab.org/](http://bjfenglab.org/)\n\nAdditional information, including pedigree formatting, is currently available at: [https://fenglab.chpc.utah.edu/cool3/manual.html](https://fenglab.chpc.utah.edu/cool3/manual.html)\n\n**Stipulation**: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.",
"label": "PP1",
"ns": "092",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Strong – LR>18.7:1\n\nPP1\\_Very Strong – LR>350:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Moderate – LR>4.3:1",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1 - LR >2.08:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165315",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165315",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---C"
},
{
"entContent": {
"_uniqueProp": "092_BS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BS1",
"ns": "092",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165313",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165313",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--J"
},
{
"entContent": {
"_uniqueProp": "092_BS4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tool COOL located on this website:[http://bjfenglab.org/](http://bjfenglab.org/)\n\nAdditional information, including pedigree formatting, is currently available at: [https://fenglab.chpc.utah.edu/cool3/manual.html](https://fenglab.chpc.utah.edu/cool3/manual.html)",
"label": "BS4",
"ns": "092",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR \\<0.05:1\n\nBS4\\_VeryStrong – LR \\<0.00285:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR \\<0.23:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting - LR 0.23-0.48:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165300",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165300",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--H"
},
{
"entContent": {
"_uniqueProp": "092_BP4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "BP4",
"ns": "092",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).\n\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\n\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165321",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165321",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--M"
},
{
"entContent": {
"_uniqueProp": "092_BP3_nuclear_BRCA1",
"additionalComments": "Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "092",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165316",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165316",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--G"
},
{
"entContent": {
"_uniqueProp": "092_BP7_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\n\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "BP7",
"ns": "092",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function _as measured by effect on mRNA transcript profile – mRNA assay only._ Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.\n\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\n\nSee Specifications Figure1A and Appendix J for additional details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165310",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165310",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--H"
},
{
"entContent": {
"_uniqueProp": "092_PM6_nuclear_BRCA1",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "092",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165309",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165309",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---B"
},
{
"entContent": {
"_uniqueProp": "092_BA1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BA1",
"ns": "092",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165308",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165308",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxqC---"
},
{
"entContent": {
"_uniqueProp": "092_PP5_nuclear_BRCA1",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "092",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165304",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165304",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--I"
},
{
"entContent": {
"_uniqueProp": "092_BP1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact. _Missense prediction not applicable_.",
"label": "BP1",
"ns": "092",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165301",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165301",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---D"
},
{
"entContent": {
"_uniqueProp": "092_BS3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9**, provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "BS3",
"ns": "092",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165299",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165299",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---_"
},
{
"entContent": {
"_uniqueProp": "092_PS4_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Case dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.",
"label": "PS4",
"ns": "092",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165296",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165296",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq----"
},
{
"entContent": {
"_uniqueProp": "092_PP2_nuclear_BRCA1",
"additionalComments": "High frequency of benign missense variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "092",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165302",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165302",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--G"
},
{
"entContent": {
"_uniqueProp": "092_PM5_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Only applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5\\_PTC codes applicable for predicted termination codon variants - organized by exon.",
"label": "PM5",
"ns": "092",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165298",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165298",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---C"
},
{
"entContent": {
"_uniqueProp": "092_PS1_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "For both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\n\nFor application of PS1 for splicing predictions, **see Specifications Table 5.** The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the previously classified pathogenic variant should also be considered before PS1 code application for splicing prediction.",
"label": "PS1",
"ns": "092",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply **PS1\\_Supporting**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165319",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165319",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--H"
},
{
"entContent": {
"_uniqueProp": "092_PS2_nuclear_BRCA1",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "092",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165318",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165318",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--A"
},
{
"entContent": {
"_uniqueProp": "092_BP5_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nSee Specifications Table7 for example application.",
"label": "BP5",
"ns": "092",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong – LR \\<0.00285:1\n\nBP5\\_Strong - LR \\<0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR \\<0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165314",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165314",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--_"
},
{
"entContent": {
"_uniqueProp": "092_PP3_nuclear_BRCA1",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications** **Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "PP3",
"ns": "092",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.\n\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\n\nSee Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165311",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165311",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--J"
},
{
"entContent": {
"_uniqueProp": "092_PM4_nuclear_BRCA1",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA1"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "092",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614165294",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614165294",
"modified": "2023-12-21T20:16:33.416Z",
"modifier": "michaelP",
"rev": "_h6SHxq---A"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011450",
"lbl": "breast-ovarian cancer, familial, susceptibility to, 1",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0011450"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/breast_ovarian_cancer_familial_1_2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/382914"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2676676"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/604370"
}
],
"definition": {
"val": "Any hereditary breast ovarian cancer syndrome in which the cause of the disease is a mutation in the BRCA1 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#predisposition",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "BRCA1 hereditary breast ovarian cancer syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, 1, multifactorial"
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, 1",
"xrefs": [
"MONDO:Lexical",
"OMIM:604370"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, type 1",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast ovarian cancer syndrome caused by mutation in BRCA1",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BROVCA1",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial, susceptibility to, 1"
},
{
"pred": "hasRelatedSynonym",
"val": "ovarian cancer, familial, susceptibility to, 1"
},
{
"pred": "hasRelatedSynonym",
"val": "susceptibility to familial breast-ovarian cancer 1"
}
],
"xrefs": [
{
"val": "GARD:12351"
},
{
"val": "MEDGEN:382914"
},
{
"val": "OMIM:604370"
},
{
"val": "UMLS:C2676676"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011450",
"name": "breast-ovarian cancer, familial, susceptibility to, 1"
},
"entId": "MONDO:0011450",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011450",
"entType": "Disease",
"ldhId": "467887429",
"ldhIri": "https://genboree.org/cspec/Disease/id/467887429",
"modified": "2025-10-07T15:44:28.239Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7WaQC---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056943390228500,
"agr": "HGNC:1100",
"alias_name": [
"BRCA1/BRCA2-containing complex, subunit 1",
"protein phosphatase 1, regulatory subunit 53",
"Fanconi anemia, complementation group S"
],
"alias_symbol": [
"RNF53",
"BRCC1",
"PPP1R53",
"FANCS"
],
"ccds_id": [
"CCDS11454",
"CCDS11455",
"CCDS11456",
"CCDS11453",
"CCDS11459"
],
"cosmic": "BRCA1",
"date_approved_reserved": "1991-02-20",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ena": [
"U14680"
],
"ensembl_gene_id": "ENSG00000012048",
"entrez_id": "672",
"gene_group": [
"Ring finger proteins",
"FA complementation groups",
"Protein phosphatase 1 regulatory subunits",
"BRCA1 A complex",
"BRCA1 B complex",
"BRCA1 C complex"
],
"gene_group_id": [
58,
548,
694,
1328,
1335,
1336
],
"hgnc_id": "HGNC:1100",
"location": "17q21.31",
"location_sortable": "17q21.31",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Breast Cancer|http://research.nhgri.nih.gov/bic/",
"Fanconi Anaemia Mutation Database|http://www2.rockefeller.edu/fanconi",
"BRCA1 database at LOVD-China|http://genomed.org/LOVD/BC/home.php?select_db=BRCA1",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/BRCA1",
"LOVD - Leiden Open Variation Database|http://proteomics.bio21.unimelb.edu.au/lovd/genes/BRCA1",
"LRG_292|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_292.xml"
],
"mane_select": [
"ENST00000357654.9",
"NM_007294.4"
],
"mgd_id": [
"MGI:104537"
],
"name": "BRCA1 DNA repair associated",
"omim_id": [
"113705"
],
"orphanet": 119068,
"prev_name": [
"breast cancer 1, early onset",
"breast cancer 1"
],
"pubmed_id": [
1676470,
25472942
],
"refseq_accession": [
"NM_007294"
],
"rgd_id": [
"RGD:2218"
],
"status": "Approved",
"symbol": "BRCA1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002ict.4",
"uniprot_ids": [
"P38398"
],
"uuid": "21978d03-2e56-4013-b4e6-eedbaaec2420",
"vega_id": "OTTHUMG00000157426"
}
},
"entId": "BRCA1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1100",
"entType": "Gene",
"ldhId": "467818961",
"ldhIri": "https://genboree.org/cspec/Gene/id/467818961",
"modified": "2021-10-14T11:36:31.267Z",
"modifier": "genbadmin",
"rev": "_h6SHyD2--L"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "092_nuclear_BRCA1",
"geneType": "nuclear",
"generalComments": "",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0011450",
"preferredTitle": "breast-ovarian cancer, familial, susceptibility to, 1"
}
],
"gene": "BRCA1",
"preferredTranscript": "NM_007294.4"
}
],
"ns": "092",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule2, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule2, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule2"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule3, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule3, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule3"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule5, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule5, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule5"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule9, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule9, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule9, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule9"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule11, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule11"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "<=1",
"getpartitionPath": "",
"label": "Rule12, Condition3",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule13, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule16, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"getpartitionPath": "",
"label": "Rule16, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Benign.Moderate"
}
],
"inference": "Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Benign.Moderate"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule20, Condition3",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Benign",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule21, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Benign",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule22"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule23, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule23"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule24"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition2",
"partitionPath": "Benign.Moderate"
}
],
"inference": "Likely Benign",
"rule": "Rule24"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule25, Condition1",
"partitionPath": "Benign.Moderate"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule25, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule25"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1530970800",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1530970800",
"modified": "2023-12-21T20:16:33.270Z",
"modifier": "michaelP",
"rev": "_h6SHyTW--e"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "BRCA1/BRCA2",
"approval": {
"step1": {
"approvalDate": "2020-12-12T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-12-13T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-04-28T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-08-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "ENIGMA BRCA1 and BRCA2",
"shortBaseName": "BRCA1/BRCA2",
"shortTitle": "ENIGMA BRCA1 and BRCA2 VCEP",
"title": "ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50087",
"entIri": "http://clinicalgenome.org/affiliation/50087",
"entType": "Organization",
"ldhId": "639508895",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508895",
"modified": "2023-08-08T12:53:03.856Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--e"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1530970787",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1530970787",
"modified": "2023-12-21T20:16:33.144Z",
"modifier": "michaelP",
"rev": "_h6SHykW--_"
},
{
"entContent": {
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA2",
"namespace": "GN093",
"releaseNotes": "",
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "mandyS",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-10-21T03:40:39.955Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"modifiedBy": "cspecAdministrator",
"name": "cspec-deleted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-01-17T16:15:03.634Z"
},
"name": "CSpec Deleted"
}
],
"tagNameSpaces": [
"093"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN093",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012933",
"lbl": "breast-ovarian cancer, familial, susceptibility to, 2",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012933"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/breast_ovarian_cancer_familial_2_2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/382625"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2675520"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/612555"
}
],
"definition": {
"val": "Any hereditary breast ovarian cancer syndrome in which the cause of the disease is a mutation in the BRCA2 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#predisposition",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "BRCA2 hereditary breast ovarian cancer syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, 2"
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, 2",
"xrefs": [
"MONDO:Lexical",
"OMIM:612555"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, type 2",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast ovarian cancer syndrome caused by mutation in BRCA2",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BROVCA2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial, susceptibility to, 2"
},
{
"pred": "hasRelatedSynonym",
"val": "ovarian cancer, familial, susceptibility to, 2"
},
{
"pred": "hasRelatedSynonym",
"val": "susceptibility to familial breast-ovarian cancer 2"
}
],
"xrefs": [
{
"val": "MEDGEN:382625"
},
{
"val": "OMIM:612555"
},
{
"val": "UMLS:C2675520"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012933",
"name": "breast-ovarian cancer, familial, susceptibility to, 2"
},
"entId": "MONDO:0012933",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012933",
"entType": "Disease",
"ldhId": "467873801",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873801",
"modified": "2025-10-07T15:44:52.543Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wx7----"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056943391277000,
"agr": "HGNC:1101",
"alias_name": [
"BRCA1/BRCA2-containing complex, subunit 2"
],
"alias_symbol": [
"FAD",
"FAD1",
"BRCC2",
"XRCC11"
],
"ccds_id": [
"CCDS9344"
],
"cosmic": "BRCA2",
"date_approved_reserved": "1994-10-17",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ena": [
"U43746"
],
"ensembl_gene_id": "ENSG00000139618",
"entrez_id": "675",
"gene_group": [
"FA complementation groups"
],
"gene_group_id": [
548
],
"hgnc_id": "HGNC:1101",
"location": "13q13.1",
"location_sortable": "13q13.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Breast Cancer|http://research.nhgri.nih.gov/bic/",
"Fanconi Anaemia Mutation Database|http://www2.rockefeller.edu/fanconi/",
"BRCA1 database at LOVD-China|http://genomed.org/LOVD/BC/home.php?select_db=BRCA2",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/BRCA2",
"LOVD - Leiden Open Variation Database|http://proteomics.bio21.unimelb.edu.au/lovd/genes/BRCA2",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/FANCD1",
"LRG_293|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_293.xml"
],
"mane_select": [
"ENST00000380152.8",
"NM_000059.4"
],
"mgd_id": [
"MGI:109337"
],
"name": "BRCA2 DNA repair associated",
"omim_id": [
"600185"
],
"orphanet": 119072,
"prev_name": [
"Fanconi anemia, complementation group D1",
"breast cancer 2, early onset",
"breast cancer 2"
],
"prev_symbol": [
"FANCD1",
"FACD",
"FANCD"
],
"pubmed_id": [
8091231,
7581463,
15057823
],
"refseq_accession": [
"NM_000059"
],
"rgd_id": [
"RGD:2219"
],
"status": "Approved",
"symbol": "BRCA2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001uub.2",
"uniprot_ids": [
"P51587"
],
"uuid": "c1732bf3-cd86-42a2-b8e3-76e8da2d317c",
"vega_id": "OTTHUMG00000017411"
}
},
"entId": "BRCA2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1101",
"entType": "Gene",
"ldhId": "467818963",
"ldhIri": "https://genboree.org/cspec/Gene/id/467818963",
"modified": "2021-10-14T11:36:31.267Z",
"modifier": "genbadmin",
"rev": "_h6SHyDu--O"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "093_nuclear_BRCA2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0012933",
"preferredTitle": "breast-ovarian cancer, familial, susceptibility to, 2"
}
],
"gene": "BRCA2",
"preferredTranscript": "NM_000059.4"
}
],
"ns": "093",
"references": []
},
"entType": "RuleSet",
"ldhId": "1530972314",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1530972314",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTG--F"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "BRCA1/BRCA2",
"approval": {
"step1": {
"approvalDate": "2020-12-12T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-12-13T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-04-28T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-08-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "ENIGMA BRCA1 and BRCA2",
"shortBaseName": "BRCA1/BRCA2",
"shortTitle": "ENIGMA BRCA1 and BRCA2 VCEP",
"title": "ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50087",
"entIri": "http://clinicalgenome.org/affiliation/50087",
"entType": "Organization",
"ldhId": "639508895",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508895",
"modified": "2023-08-08T12:53:03.856Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--e"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1530972301",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1530972301",
"modified": "2023-01-27T21:47:10.559Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyj6--F"
},
{
"entContent": {
"description": "",
"namespace": "GN094",
"releaseNotes": "",
"shortTitle": "RASopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-03T14:32:08.907Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-submitted",
"prevState": "Classification Rules In Prep",
"timeStamp": "2023-06-08T15:00:00.782Z"
},
"name": "Classification Rules Submitted"
},
{
"current": false,
"event": {
"name": "classified-rules-withdrawn",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-05-01T16:55:59.177Z"
},
"name": "Classification Rules In Prep"
},
{
"current": false,
"event": {
"name": "classified-rules-reviewed",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-03-21T18:09:32.828Z"
},
"name": "Classification Rules In Prep"
},
{
"current": true,
"event": {
"name": "classified-rules-approved",
"prevState": "Classification Rules Submitted",
"timeStamp": "2023-09-06T21:13:49.978Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"094"
],
"title": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN094",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0014693",
"lbl": "Noonan syndrome 10",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/noonan_syndrome_10"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/902892"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C4225280"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060588"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C176938"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/616564"
}
],
"definition": {
"val": "Any Noonan syndrome in which the cause of the disease is a mutation in the LZTR1 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "LZTR1 Noonan syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "NS10",
"xrefs": [
"DOID:0060588",
"MONDO:Lexical",
"NCIT:C176938",
"OMIM:616564"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome 10",
"xrefs": [
"DOID:0060588",
"MONDO:Lexical",
"NCIT:C176938",
"OMIM:616564"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome caused by mutation in LZTR1",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome type 10",
"xrefs": [
"MONDORULE:2"
]
}
],
"xrefs": [
{
"val": "DOID:0060588"
},
{
"val": "GARD:16139"
},
{
"val": "MEDGEN:902892"
},
{
"val": "NCIT:C176938"
},
{
"val": "OMIM:616564"
},
{
"val": "UMLS:C4225280"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0014693",
"name": "Noonan syndrome 10"
},
"entId": "MONDO:0014693",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0014693",
"entType": "Disease",
"ldhId": "467871630",
"ldhIri": "https://genboree.org/cspec/Disease/id/467871630",
"modified": "2025-10-07T15:45:21.281Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XONW---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0011531",
"lbl": "Noonan syndrome 2",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/noonan_syndrome_2"
},
{
"pred": "http://www.w3.org/2000/01/rdf-schema#seeAlso",
"val": "https://rarediseases.info.nih.gov/diseases/10698/noonan-syndrome-2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/344290"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C548081"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C1854469"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_0060580"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C176930"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/605275"
}
],
"subsets": [
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "NS2",
"xrefs": [
"DOID:0060580",
"MONDO:Lexical",
"NCIT:C176930",
"OMIM:605275"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome 2",
"xrefs": [
"DOID:0060580",
"MONDO:Lexical",
"NCIT:C176930",
"OMIM:605275"
]
},
{
"pred": "hasExactSynonym",
"val": "Noonan syndrome type 2",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan syndrome autosomal recessive",
"xrefs": [
"GARD:0010698"
]
},
{
"pred": "hasRelatedSynonym",
"val": "Noonan syndrome, autosomal recessive"
},
{
"pred": "hasRelatedSynonym",
"val": "autosomal recessive Noonan syndrome",
"xrefs": [
"GARD:0010698"
]
}
],
"xrefs": [
{
"val": "DOID:0060580"
},
{
"val": "GARD:10698"
},
{
"val": "MEDGEN:344290"
},
{
"val": "MESH:C548081"
},
{
"val": "NCIT:C176930"
},
{
"val": "OMIM:605275"
},
{
"val": "UMLS:C1854469"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0011531",
"name": "Noonan syndrome 2"
},
"entId": "MONDO:0011531",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0011531",
"entType": "Disease",
"ldhId": "467887358",
"ldhIri": "https://genboree.org/cspec/Disease/id/467887358",
"modified": "2025-10-07T15:44:29.760Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wbq----"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056952681660400,
"agr": "HGNC:6742",
"alias_symbol": [
"LZTR-1",
"BTBD29"
],
"ccds_id": [
"CCDS33606"
],
"cosmic": "LZTR1",
"date_approved_reserved": "1999-10-19",
"date_modified": "2021-05-26",
"date_name_changed": "2016-07-04",
"ena": [
"D38496"
],
"ensembl_gene_id": "ENSG00000099949",
"entrez_id": "8216",
"gene_group": [
"BTB domain containing"
],
"gene_group_id": [
861
],
"hgnc_id": "HGNC:6742",
"location": "22q11.21",
"location_sortable": "22q11.21",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"LRG_989|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_989.xml"
],
"mane_select": [
"ENST00000646124.2",
"NM_006767.4"
],
"mgd_id": [
"MGI:1914113"
],
"name": "leucine zipper like transcription regulator 1",
"omim_id": [
"600574"
],
"orphanet": 369810,
"prev_name": [
"leucine-zipper-like transcriptional regulator 1"
],
"pubmed_id": [
7633402,
16356934
],
"refseq_accession": [
"NM_006767"
],
"rgd_id": [
"RGD:1309100"
],
"status": "Approved",
"symbol": "LZTR1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002zto.4",
"uniprot_ids": [
"Q8N653"
],
"uuid": "85661653-a11d-406e-b8ec-76eff50e8754",
"vega_id": "OTTHUMG00000150878"
}
},
"entId": "LZTR1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6742",
"entType": "Gene",
"ldhId": "467836282",
"ldhIri": "https://genboree.org/cspec/Gene/id/467836282",
"modified": "2021-10-14T11:36:49.428Z",
"modifier": "genbadmin",
"rev": "_h6SHzR2---"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "094_nuclear_LZTR1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0011531",
"preferredTitle": "Noonan syndrome 2"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0014693",
"preferredTitle": "Noonan syndrome 10"
}
],
"gene": "LZTR1",
"preferredTranscript": "NM_006767.4"
}
],
"ns": "094",
"references": []
},
"entType": "RuleSet",
"ldhId": "1532496151",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1532496151",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--N"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2017-07-30T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "RASopathy",
"shortBaseName": "RASopathy",
"shortTitle": "RASopathy VCEP",
"title": "RASopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50021",
"entIri": "http://clinicalgenome.org/affiliation/50021",
"entType": "Organization",
"ldhId": "135637642",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637642",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyD6--J"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1532496138",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1532496138",
"modified": "2023-09-06T21:13:50.213Z",
"modifier": "sharriso",
"rev": "_h6SHyk---_"
},
{
"entContent": {
"description": "",
"namespace": "GN095",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-30T01:28:32.222Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:14:44.416Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-08-18T15:45:30.029Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"095"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYBPC3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN095",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005045",
"lbl": "hypertrophic cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5962"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypertrophic_cardiomyopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_hypertrophic_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020871"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1830681485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2881"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002312"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/233873004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_11984"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34449"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000538"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#narrowMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#relatedMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
}
],
"definition": {
"val": "A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.",
"xrefs": [
"NCIT:C34449"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hypertrophic cardiomyopathy",
"xrefs": [
"DOID:11984",
"NCIT:C34449",
"icd11.foundation:1830681485"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic obstructive cardiomyopathy",
"xrefs": [
"DOID:11984"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic subaortic stenosis"
},
{
"pred": "hasExactSynonym",
"val": "obstructive hypertrophic cardiomyopathy"
},
{
"pred": "hasNarrowSynonym",
"val": "familial hypertrophic cardiomyopathy"
},
{
"pred": "hasRelatedSynonym",
"val": "HCM - hypertrophic cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:11984"
},
{
"val": "EFO:0000538"
},
{
"val": "HP:0001639"
},
{
"val": "ICD10CM:I42.1"
},
{
"val": "ICD10CM:I42.2"
},
{
"val": "ICD9:425.1"
},
{
"val": "ICD9:425.11"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2881"
},
{
"val": "MESH:D002312"
},
{
"val": "MedDRA:10020871"
},
{
"val": "NANDO:1200286"
},
{
"val": "NANDO:1200288"
},
{
"val": "NANDO:2100054"
},
{
"val": "NANDO:2200229"
},
{
"val": "NANDO:2201042"
},
{
"val": "NCIT:C34449"
},
{
"val": "Orphanet:217569"
},
{
"val": "SCTID:233873004"
},
{
"val": "UMLS:C0007194"
},
{
"val": "icd11.foundation:1830681485"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005045",
"name": "hypertrophic cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005045",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005045",
"entType": "Disease",
"ldhId": "135641999",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641999",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9FG---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056955050393600,
"agr": "HGNC:7551",
"alias_symbol": [
"FHC",
"cMyBP-C"
],
"ccds_id": [
"CCDS53621"
],
"date_approved_reserved": "1995-05-30",
"date_modified": "2021-05-26",
"date_name_changed": "2019-10-02",
"ena": [
"X84075"
],
"ensembl_gene_id": "ENSG00000134571",
"entrez_id": "4607",
"gene_group": [
"I-set domain containing",
"Myosin binding proteins"
],
"gene_group_id": [
593,
658
],
"hgnc_id": "HGNC:7551",
"iuphar": "objectId:2880",
"location": "11p11.2",
"location_sortable": "11p11.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"FHC Mutation Database|http://www.angis.org.au/Databases/Heart/heartbreak.html",
"LRG_386|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_386.xml"
],
"mane_select": [
"ENST00000545968.6",
"NM_000256.3"
],
"mgd_id": [
"MGI:102844"
],
"name": "myosin binding protein C3",
"omim_id": [
"600958"
],
"orphanet": 123595,
"prev_name": [
"myosin-binding protein C, cardiac"
],
"prev_symbol": [
"CMH4"
],
"pubmed_id": [
7744002,
8358441
],
"refseq_accession": [
"NM_000256"
],
"rgd_id": [
"RGD:1305950"
],
"status": "Approved",
"symbol": "MYBPC3",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc058bdz.1",
"uniprot_ids": [
"Q14896"
],
"uuid": "780d9df7-6d28-45af-98d3-8c15e9ab697e",
"vega_id": "OTTHUMG00000166986"
}
},
"entId": "MYBPC3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7551",
"entType": "Gene",
"ldhId": "467841063",
"ldhIri": "https://genboree.org/cspec/Gene/id/467841063",
"modified": "2021-10-14T11:36:54.249Z",
"modifier": "genbadmin",
"rev": "_h6SHzom--C"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "095_nuclear_MYBPC3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0005045",
"preferredTitle": "hypertrophic cardiomyopathy"
}
],
"gene": "MYBPC3",
"preferredTranscript": "NM_000256.3"
}
],
"ns": "095",
"references": []
},
"entType": "RuleSet",
"ldhId": "1535304693",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535304693",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--Q"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2017-04-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cardiomyopathy",
"shortBaseName": "CMP",
"shortTitle": "Cardiomyopathy VCEP",
"title": "Cardiomyopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50002",
"entIri": "http://clinicalgenome.org/affiliation/50002",
"entType": "Organization",
"ldhId": "135637627",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637627",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--U"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535304680",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535304680",
"modified": "2024-03-25T21:14:44.521Z",
"modifier": "makelly2",
"rev": "_h6SHyk---R"
},
{
"entContent": {
"namespace": "GN096",
"releaseNotes": "",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer Specification",
"specificationSource": "",
"states": [
{
"current": true,
"event": {
"modifiedBy": "meganholdren",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-11-30T15:49:10.369Z"
},
"name": "Classification Rules In Prep"
}
],
"tagNameSpaces": [
"096"
],
"title": "ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN096",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016419",
"lbl": "hereditary breast carcinoma",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016419"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hereditary_breast_carcinoma"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/87542"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/C562840"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/254843006"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0346153"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C4503"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_227535"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/114480"
}
],
"comments": [
"Editor note: check w clingen before merge https://github.com/monarch-initiative/mondo/issues/84"
],
"definition": {
"val": "Breast carcinoma that has developed in relatives of patients with history of breast carcinoma.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "breast cancer susceptibility, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, early-onset, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, invasive ductal, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, lobular, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, male, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, protection against, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, somatic"
},
{
"pred": "hasExactSynonym",
"val": "breast cancer, susceptibility to, autosomal dominant, somatic mutation"
},
{
"pred": "hasExactSynonym",
"val": "familial breast cancer",
"xrefs": [
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial breast carcinoma",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "familial cancer of the breast",
"xrefs": [
"NCIT:C4503"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast cancer",
"xrefs": [
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast carcinoma",
"xrefs": [
"MONDO:patterns/hereditary",
"NCIT:C4503",
"Orphanet:227535"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial"
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial Male"
}
],
"xrefs": [
{
"val": "GARD:17142"
},
{
"val": "ICD10CM:C50.2"
},
{
"val": "ICD10CM:C50.3"
},
{
"val": "ICD10CM:C50.6"
},
{
"val": "MEDGEN:87542"
},
{
"val": "MESH:C562840"
},
{
"val": "NCIT:C4503"
},
{
"val": "OMIM:114480"
},
{
"val": "Orphanet:227535"
},
{
"val": "SCTID:254843006"
},
{
"val": "UMLS:C0346153"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016419",
"name": "hereditary breast carcinoma"
},
"entId": "MONDO:0016419",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016419",
"entType": "Disease",
"ldhId": "467880845",
"ldhIri": "https://genboree.org/cspec/Disease/id/467880845",
"modified": "2025-10-07T15:45:51.651Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XrmW---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0019391",
"lbl": "Fanconi anemia",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5682"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0019391"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0018234"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0019289"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0100137"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#should_conform_to",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/OMIM_phenotypic_series.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10055206"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/41967"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D005199"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/30575002"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0015625"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_13636"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C62505"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_84"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/phenotypicSeries/PS227650"
}
],
"definition": {
"val": "Fanconi anemia (FA) is a hereditary DNA repair disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors.",
"xrefs": [
"Orphanet:84"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_disorder",
"http://purl.obolibrary.org/obo/mondo#ordo_malformation_syndrome",
"http://purl.obolibrary.org/obo/mondo#orphanet_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "Fanconi anemia",
"xrefs": [
"DOID:13636",
"NCIT:C62505",
"OMIMPS:227650",
"Orphanet:84"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi pancytopenia",
"xrefs": [
"DOID:13636",
"Orphanet:84"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi panmyelopathy",
"xrefs": [
"DOID:13636"
]
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "Fanconi's anaemia",
"xrefs": [
"DOID:13636"
]
},
{
"pred": "hasExactSynonym",
"val": "Fanconi's anemia",
"xrefs": [
"DOID:13636",
"NCIT:C62505"
]
},
{
"pred": "hasExactSynonym",
"val": "Panmyelopathy, Fanconi",
"xrefs": [
"NCIT:C62505"
]
},
{
"pred": "hasExactSynonym",
"val": "pancytopenia, congenital",
"xrefs": [
"NCIT:C62505"
]
},
{
"pred": "hasExactSynonym",
"val": "primary erythroid hypoplasia",
"xrefs": [
"NCIT:C62505"
]
}
],
"xrefs": [
{
"val": "DOID:13636"
},
{
"val": "GARD:6425"
},
{
"val": "ICD9:284.09"
},
{
"val": "MEDGEN:41967"
},
{
"val": "MESH:D005199"
},
{
"val": "MedDRA:10055206"
},
{
"val": "NANDO:1200303"
},
{
"val": "NANDO:1200891"
},
{
"val": "NANDO:2200652"
},
{
"val": "NCIT:C62505"
},
{
"val": "NORD:1132"
},
{
"val": "OMIMPS:227650"
},
{
"val": "Orphanet:84"
},
{
"val": "SCTID:30575002"
},
{
"val": "UMLS:C0015625"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0019391",
"name": "Fanconi anemia"
},
"entId": "MONDO:0019391",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0019391",
"entType": "Disease",
"ldhId": "467891379",
"ldhIri": "https://genboree.org/cspec/Disease/id/467891379",
"modified": "2025-10-07T15:46:43.366Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7YeXq---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0016248",
"lbl": "familial ovarian cancer",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4889"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0016248"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0015981"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#excluded_subClassOf",
"val": "http://purl.obolibrary.org/obo/MONDO_0018365"
},
{
"pred": "http://purl.org/dc/terms/conformsTo",
"val": "http://purl.obolibrary.org/obo/mondo/patterns/hereditary.yaml"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1484739866"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/1803368"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C5679802"
}
],
"definition": {
"val": "An instance of ovarian cancer that is caused by an inherited modification of the individual's genome.",
"xrefs": [
"MONDO:patterns/hereditary"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "familial ovarian cancer",
"xrefs": [
"icd11.foundation:1484739866"
]
},
{
"pred": "hasExactSynonym",
"val": "familial ovarian malignant tumor"
},
{
"pred": "hasExactSynonym",
"synonymType": "http://purl.obolibrary.org/obo/OMO_0003005",
"val": "familial ovarian malignant tumour"
},
{
"pred": "hasExactSynonym",
"val": "hereditary ovarian cancer",
"xrefs": [
"MONDO:patterns/hereditary"
]
}
],
"xrefs": [
{
"val": "GARD:20467"
},
{
"val": "MEDGEN:1803368"
},
{
"val": "Orphanet:213517"
},
{
"val": "UMLS:C5679802"
},
{
"val": "icd11.foundation:1484739866"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0016248",
"name": "familial ovarian cancer"
},
"entId": "MONDO:0016248",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0016248",
"entType": "Disease",
"ldhId": "467881877",
"ldhIri": "https://genboree.org/cspec/Disease/id/467881877",
"modified": "2025-10-07T15:45:48.459Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7XolS---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056958847287300,
"agr": "HGNC:9820",
"alias_symbol": [
"RAD51L2",
"FANCO"
],
"ccds_id": [
"CCDS11611",
"CCDS45745"
],
"date_approved_reserved": "1998-02-26",
"date_modified": "2021-04-13",
"date_name_changed": "2013-07-02",
"ena": [
"AF029670"
],
"ensembl_gene_id": "ENSG00000108384",
"entrez_id": "5889",
"gene_group": [
"FA complementation groups"
],
"gene_group_id": [
548
],
"hgnc_id": "HGNC:9820",
"location": "17q22",
"location_sortable": "17q22",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Fanconi Anaemia Mutation Database|http://www2.rockefeller.edu/fanconi",
"LRG_314|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_314.xml"
],
"mane_select": [
"ENST00000337432.9",
"NM_058216.3"
],
"mgd_id": [
"MGI:2150020"
],
"name": "RAD51 paralog C",
"omim_id": [
"602774"
],
"orphanet": 229784,
"prev_name": [
"RAD51 (S. cerevisiae) homolog C",
"RAD51 homolog C (S. cerevisiae)"
],
"pubmed_id": [
9469824,
22167183
],
"refseq_accession": [
"NM_058216"
],
"rgd_id": [
"RGD:1563765"
],
"status": "Approved",
"symbol": "RAD51C",
"ucsc_id": "uc002iwu.5",
"uniprot_ids": [
"O43502"
],
"uuid": "9fc13051-8d8d-4dcb-979e-c3ba3869be9e",
"vega_id": "OTTHUMG00000141292"
}
},
"entId": "RAD51C",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9820",
"entType": "Gene",
"ldhId": "467847530",
"ldhIri": "https://genboree.org/cspec/Gene/id/467847530",
"modified": "2021-10-14T11:37:00.424Z",
"modifier": "genbadmin",
"rev": "_h6SHzoy--F"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "096_nuclear_RAD51C",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0016248",
"preferredTitle": "familial ovarian cancer"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0016419",
"preferredTitle": "hereditary breast carcinoma"
},
{
"preferredModeOfInheritance": "Autosomal recessive inheritance",
"preferredMondoId": "MONDO:0019391",
"preferredTitle": "Fanconi anemia"
}
],
"gene": "RAD51C",
"preferredTranscript": "NM_058216.3"
}
],
"ns": "096",
"references": []
},
"entType": "RuleSet",
"ldhId": "1535377192",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535377192",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTK--O"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "HBOP",
"approval": {
"step1": {
"approvalDate": "2018-11-28T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2019-10-31T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2022-01-20T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2022-01-25T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Hereditary Breast, Ovarian and Pancreatic Cancer",
"shortBaseName": "HBOP",
"shortTitle": "Hereditary Breast, Ovarian and Pancreatic Cancer VCEP",
"title": "Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50039",
"entIri": "http://clinicalgenome.org/affiliation/50039",
"entType": "Organization",
"ldhId": "639508880",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508880",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEq--T"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535377178",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535377178",
"modified": "2022-11-30T15:49:13.920Z",
"modifier": "meganholdren",
"rev": "_h6SHyju--D"
},
{
"entContent": {
"approvedOn": "2023-12-21T20:17:19.708Z",
"description": "ClinGen Internal VCEP ACMG/AMP specifications for BRCA1 and BRCA2",
"namespace": "GN097",
"releaseNotes": "Updates in v1.1:\n\nUpdated web-link for suggested co-segregation analysis tool (COOL)\n\nUpdated assigned PVS1 codes for some variants in Specifications Table 4\n\nUpdated assigned PS3/BS3 codes for some variants in Specifications Table 9, including results updates from interim Findlay report\n\nCorrected typos and errors\n\nAdded Supplementary table 16 - mRNA assay evidence used to highlight IVS1/2 variants eligible for PVS1 (RNA) code\n\nClarified code combinations table in Specifications document: any conflicting pathogenic and benign evidence codes should be resolved using approach 2 (points system)",
"releasedUnderRevision": true,
"shortTitle": "ENIGMA BRCA1 and BRCA2 Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-01T05:58:55.256Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2023-11-23T06:15:12.753Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-04-10T20:53:02.886Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": false,
"event": {
"modifiedBy": "sharriso",
"name": "pilot-rules-approved",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2023-12-14T17:33:20.948Z"
},
"name": "Approved For Release"
},
{
"current": true,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-released",
"prevState": "Approved For Release",
"timeStamp": "2023-12-21T20:17:19.708Z"
},
"name": "Released"
},
{
"current": false,
"event": {
"modifiedBy": "michaelP",
"name": "cspec-reopened",
"prevState": "Released",
"timeStamp": "2023-11-23T06:07:50.561Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"097"
],
"title": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0",
"version": "1.1.0",
"versioned": true
},
"entId": "GN097",
"entType": "SequenceVariantInterpretation",
"ld": {
"CriteriaCode": [
{
"entContent": {
"_uniqueProp": "097_PP4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nSee Specifications Table7 for example application.",
"label": "PP4",
"ns": "097",
"originalACMGSummary": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.",
"sepioID": "SEPIO-CG:99036",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0239",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "002",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "005",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Strong – LR>18.7:1\n\nPP4\\_Very Strong – LR>350:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0018",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4\\_Moderate – LR>4.3:1\n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0063",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.\n\nPP4 - LR >2.08:1 \n\nCombined LR 1.00-2.08 is not informative (PP4 not applicable).\n\nSee Specifications Table7 and Appendix B for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166140",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166140",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpm--B"
},
{
"entContent": {
"_uniqueProp": "097_BP3_nuclear_BRCA2",
"additionalComments": "Captured by bioinformatic tool prediction, and domain analysis. See Appendix J for details",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "BP3",
"ns": "097",
"originalACMGSummary": "In frame-deletions/insertions in a repetitive region without a known function.",
"sepioID": "SEPIO-CG:99045",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0212",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0210",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0074",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0211",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0081",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166139",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166139",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--D"
},
{
"entContent": {
"_uniqueProp": "097_PVS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Very Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5\\_PTC code (See Appendix D for details).\n\n**See Specifications Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the** _**BRCA1**_ **and** _**BRCA2**_ **PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon.** See Appendix Figure 5,6 and Table 5 for further justification.\n\nSee **Specifications** **Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.",
"label": "PVS1",
"ns": "097",
"originalACMGSummary": "Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.\nCaveats:\n * Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).\n * Use caution interpreting LOF variants at the extreme 3’ end of a gene.\n * Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.\n * Use caution in the presence of multiple transcripts.",
"sepioID": "SEPIO-CG:99022",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0245",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)",
"Use caution interpreting LOF variants at the extreme 3' end of a gene",
"Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact",
"Use caution in the presence of multiple transcripts"
]
},
"applicability": "Applicable",
"id": "0017",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0020",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0026",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "001",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166130",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166130",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpm---"
},
{
"entContent": {
"_uniqueProp": "097_PM1_nuclear_BRCA2",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4). ",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM1",
"ns": "097",
"originalACMGSummary": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.",
"sepioID": "SEPIO-CG:99027",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0230",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0015",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0028",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "006",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0054",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166129",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166129",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--P"
},
{
"entContent": {
"_uniqueProp": "097_PP5_nuclear_BRCA2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "PP5",
"ns": "097",
"originalACMGSummary": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99049",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166127",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166127",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--O"
},
{
"entContent": {
"_uniqueProp": "097_BS2_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nSee **Specifications Table 8** for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.\n\nAlso see **Specifications Table 8** for additional stipulations.",
"label": "BS2",
"ns": "097",
"originalACMGSummary": "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
"sepioID": "SEPIO-CG:99040",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0091",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000357",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0224",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0069",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2 = ≥ 4 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0098",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Moderate = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0076",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See **Specifications Table 8** for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.\n\nBS2\\_Supporting = 1 points",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166126",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166126",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxq---D"
},
{
"entContent": {
"_uniqueProp": "097_BP1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact. _Missense prediction not applicable_.",
"label": "BP1",
"ns": "097",
"originalACMGSummary": "Missense variant in a gene for which primarily truncating variants are known to cause disease.",
"sepioID": "SEPIO-CG:99043",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0206",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0204",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0075",
"instructionsToUse": "",
"specificationType": [
"Gene-specific",
"Strength"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "**Apply BP1\\_Strong** for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0205",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0082",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166124",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166124",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--L"
},
{
"entContent": {
"_uniqueProp": "097_BS4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tool COOL located on this website: [http://bjfenglab.org/](http://bjfenglab.org/)\n\nAdditional information, including pedigree formatting, is currently available at: [https://fenglab.chpc.utah.edu/cool3/manual.html](https://fenglab.chpc.utah.edu/cool3/manual.html)",
"label": "BS4",
"ns": "097",
"originalACMGSummary": "Lack of segregation in affected members of a family.\nCaveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
"sepioID": "SEPIO-CG:99042",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0229",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0227",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"The presence of phenocopies for common phenotypes (i.e., cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation."
]
},
"applicability": "Applicable",
"id": "0071",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4 - LR \\<0.05:1\n\nBS4\\_VeryStrong – LR \\<0.00285:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0228",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Moderate - LR \\<0.23:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0077",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nBS4\\_Supporting - LR 0.23-0.48:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166123",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166123",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--K"
},
{
"entContent": {
"_uniqueProp": "097_BS3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9,** provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "BS3",
"ns": "097",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.",
"sepioID": "SEPIO-CG:99041",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0226",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0225",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0072",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of no damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0100",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0001327",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0085",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166122",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166122",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--B"
},
{
"entContent": {
"_uniqueProp": "097_PS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "For both missense and splicing scenarios, (Likely) Pathogenic variant classification should be assigned using VCEP specifications.\n\nFor application of PS1 for splicing predictions, **see Specifications Table 5.** The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant. For an exonic variant, predicted or proven functional effect of missense substitution/s encoded by the variant and the established pathogenic variant should also be considered before PS1 code application for splicing prediction.",
"label": "PS1",
"ns": "097",
"originalACMGSummary": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99023",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0240",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0021",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Beware of changes that impact splicing rather than at the amino acid/protein level"
],
"Example": [
"Val=>Leu caused by either G>C or G>T in the same codon"
]
},
"applicability": "Applicable",
"id": "0050",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply **PS1**, for predicted **missense** substitutions, where a previously classified **pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1**, for exonic and intronic variants with same predicted impact on **splicing,** as a previously classified **pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. \n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0046",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply **PS1\\_Moderate**, for predicted **missense** substitutions, where a previously classified **likely pathogenic** variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).\n\nApply **PS1\\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0036",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic** variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.\n\nSee Specifications Table 5 and Appendix E, J and K for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166142",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166142",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--R"
},
{
"entContent": {
"_uniqueProp": "097_BP7_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained. Not applicable for missense variants inside a (potentially) clinically important functional domain as they may still impact protein function through the amino acid change.\n\nFollowing convention, this code is applied in addition to BP4 (no splicing prediction, Splice AI ≤0.1) to capture the low prior probability of pathogenicity of silent variants. Nucleotide conservation is not considered relevant. See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "BP7",
"ns": "097",
"originalACMGSummary": "A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.",
"sepioID": "SEPIO-CG:99049",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0221",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0219",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0065",
"instructionsToUse": "",
"specificationType": [
"General recommendation",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Well-established in vitro or in vivo functional studies shows no damaging effect on protein function _as measured by effect on mRNA transcript profile – mRNA assay only._ Apply as BP7\\_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0220",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0079",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"General recommendation"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.\n\nIntronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.\n\nSee Specifications Figure1A and Appendix J for additional details.\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166133",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166133",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--R"
},
{
"entContent": {
"_uniqueProp": "097_BA1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Stand Alone",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BA1",
"ns": "097",
"originalACMGSummary": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
"sepioID": "SEPIO-CG:99038",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Applicable",
"id": "0087",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0201",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0202",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0203",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0089",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166131",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166131",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpm--_"
},
{
"entContent": {
"_uniqueProp": "097_PM5_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Only applied to genomic PTC changes (not splicing). Weight determined by exon where the termination codon occurs (may not be the same exon as the variant position). See Specifications Table 4, provided as a separate searchable excel file, for PM5\\_PTC codes applicable for predicted termination codon variants - organized by exon.",
"label": "PM5",
"ns": "097",
"originalACMGSummary": "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.\nExample: Arg156His is pathogenic; now you observe Arg156Cys.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
"sepioID": "SEPIO-CG:99031",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0234",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0047",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0056",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Examples": [
"Arg156His is pathogenic; now you observe Arg156Cys"
]
},
"applicability": "Applicable",
"id": "008",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0048",
"instructionsToUse": "",
"specificationType": [
"Other"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5\\_PTC code strengths applicable per exon. See Appendix D for additional details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166121",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166121",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--N"
},
{
"entContent": {
"_uniqueProp": "097_BP4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "BP4",
"ns": "097",
"originalACMGSummary": "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99046",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0215",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0213",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0066",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0214",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0080",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).\n\nSilent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).\n\nIntronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).\n\nAs justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166144",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166144",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--E"
},
{
"entContent": {
"_uniqueProp": "097_PP1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Segregation Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Recommend use of online tool COOL located on this website: [http://bjfenglab.org/](http://bjfenglab.org/)\n\nAdditional information, including pedigree formatting, is currently available at: [https://fenglab.chpc.utah.edu/cool3/manual.html](https://fenglab.chpc.utah.edu/cool3/manual.html)\n\n**Stipulation**: to apply code as Pathogenic Very Strong, VUS should have bioinformatically predicted (or experimentally proven) effect on protein or mRNA splicing. If co-segregation score is from a single family, or several families from an isolated population, assess the possibility of a different causative pathogenic variant.",
"label": "PP1",
"ns": "097",
"originalACMGSummary": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\nNote: May be used as stronger evidence with increasing segregation data.",
"sepioID": "SEPIO-CG:99033",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0236",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0042",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0023",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Strong – LR>18.7:1\n\nPP1\\_Very Strong – LR>350:1",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0040",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1\\_Moderate – LR>4.3:1",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"May be used as stronger evidence with increasing segregation data"
]
},
"applicability": "Applicable",
"id": "0060",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.\n\nApply weight as per Bayes Score:\n\nPP1 - LR >2.08:1",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166138",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166138",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxq---E"
},
{
"entContent": {
"_uniqueProp": "097_BS1_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately.\n\nDo not apply if read depth \\<20. Do not apply to well-established pathogenic founder variants.",
"label": "BS1",
"ns": "097",
"originalACMGSummary": "Allele frequency is greater than expected for disorder.",
"sepioID": "SEPIO-CG:99039",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not Applicable",
"id": "0090",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0222",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0070",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0223",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0086",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166136",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166136",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxqC--C"
},
{
"entContent": {
"_uniqueProp": "097_PM3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Co-occurrent P or LP variant should be assigned classification using VCEP specifications. \n\nVariant under assessment must be sufficiently rare (meet PM2\\_Supporting, or PM2 not applicable).\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.\n\nFor related individuals score only most severe presentation.\n\nAlso see **Specifications Table 6** for additional stipulations",
"label": "PM3",
"ns": "097",
"originalACMGSummary": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.",
"sepioID": "SEPIO-CG:99029",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0232",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0038",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0058",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Strong = ≥4 points",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"This requires testing of parents (or offspring) to determine phase."
]
},
"applicability": "Applicable",
"id": "007",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3 = 2 points",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0027",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:\n\n(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis _≤5yr_.\n\n(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.\n\nSee **Specifications Table 6** for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.\n\nPM3\\_Supporting = 1 point",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166128",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166128",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--P"
},
{
"entContent": {
"_uniqueProp": "097_PM2_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth \\<25 at region around the variant.",
"label": "PM2",
"ns": "097",
"originalACMGSummary": "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.\nCaveat: Population data for indels may be poorly called by next generation sequencing.",
"sepioID": "SEPIO-CG:99028",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0231",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0044",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0013",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Population data for insertions/deletions may be poorly called by next-generation sequencing."
]
},
"applicability": "Not Applicable",
"id": "0011",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0030",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166118",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166118",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--I"
},
{
"entContent": {
"_uniqueProp": "097_BP5_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Use in the context of clinically calibrated evidence types, with sufficient detail to review data sources, types and weights. Published data points may include co-segregation with disease, co-occurrence with a pathogenic variant in the same gene, reported family history, breast tumor pathology, and case-control data. Can also apply for unpublished data, where there is no appropriate ACMG/AMP code. Assign weight based on combined LR for clinical data.\n\nSee Specifications Table7 for example application.",
"label": "BP5",
"ns": "097",
"originalACMGSummary": "Variant found in a case with an alternate molecular basis for disease.",
"sepioID": "SEPIO-CG:99047",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0218",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0216",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0073",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_VeryStrong – LR \\<0.00285:1\n\nBP5\\_Strong - LR \\<0.05:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0217",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5\\_Moderate - LR \\<0.23:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Applicable",
"id": "0078",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.\n\nBP5 - LR 0.23-0.48:1\n\nNot applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166137",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166137",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi---"
},
{
"entContent": {
"_uniqueProp": "097_PS3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications Figure 1C** for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. Do not apply when conflicting results are present from well-established assays with sufficient controls, which cannot be explained by experimental design.\n\nSee **Specifications Figure 1B** for process to apply codes for splicing data, in content of location and predicted bioinformatic impact of the variant, and adaptive weighting according to assay methodology and proportion of functional transcript retained.\n\nSee **Specifications Table 9,** provided as a separate file in excel format to facilitate searches and look-ups by variant c. and p. nomenclature. It includes PS3 and BS3 code recommendations and rationale for code application of published functional assays data that has been calibrated, and considered against predicted/reported splicing. This is not an exhaustive list; there will be ongoing consideration of additional published functional assay results.",
"label": "PS3",
"ns": "097",
"originalACMGSummary": "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.\nNote: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
"sepioID": "SEPIO-CG:99025",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0242",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0031",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established."
]
},
"applicability": "Applicable",
"id": "0052",
"instructionsToUse": "",
"specificationType": [
"General recommendation"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.\n\nWell-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0039",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0045",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166135",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166135",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpm--A"
},
{
"entContent": {
"_uniqueProp": "097_PM6_nuclear_BRCA2",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM6",
"ns": "097",
"originalACMGSummary": "Assumed de novo, but without confirmation of paternity and maternity.",
"sepioID": "SEPIO-CG:99032",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0235",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0014",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0037",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0010",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0022",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166132",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166132",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--Q"
},
{
"entContent": {
"_uniqueProp": "097_PS4_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "Population Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "Case dataset should be ethnicity and country-matched to control dataset. If case-control LR estimates are available for a given dataset, these should be used in preference to case-control OR data, under code PP4 (or BP5, if appropriate). Do not use Proband Counting as originally described.",
"label": "PS4",
"ns": "097",
"originalACMGSummary": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.\nNote 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.\nNote 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
"sepioID": "SEPIO-CG:99026",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0243",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0029",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.",
"In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence."
]
},
"applicability": "Applicable",
"id": "0053",
"instructionsToUse": "",
"specificationType": [
"Clarification",
"Gene-specific"
],
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0057",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0032",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166119",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166119",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--N"
},
{
"entContent": {
"_uniqueProp": "097_PM4_nuclear_BRCA2",
"additionalComments": "Considered as component of bioinformatic analysis (PP3/BP4).",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Moderate",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PM4",
"ns": "097",
"originalACMGSummary": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.",
"sepioID": "SEPIO-CG:99030",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0233",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0012",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0035",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "009",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0059",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166117",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166117",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--M"
},
{
"entContent": {
"_uniqueProp": "097_BP6_nuclear_BRCA2",
"additionalComments": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"applicability": "Not Applicable for this VCEP",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Other Database",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "",
"label": "BP6",
"ns": "097",
"originalACMGSummary": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",
"references": [
{
"id": "29543229",
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/29543229"
}
],
"sepioID": "SEPIO-CG:99048",
"strengthDescriptor": [
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"instructionsToUse": "",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000326",
"text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166143",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166143",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--A"
},
{
"entContent": {
"_uniqueProp": "097_PS2_nuclear_BRCA2",
"additionalComments": "BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Strong",
"evidenceCategory": "De novo Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PS2",
"ns": "097",
"originalACMGSummary": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
"sepioID": "SEPIO-CG:99024",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0241",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0016",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Notes": [
"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity."
]
},
"applicability": "Not applicable",
"id": "0051",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "004",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0043",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166141",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166141",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxq---F"
},
{
"entContent": {
"_uniqueProp": "097_PP3_nuclear_BRCA2",
"additionalComments": "",
"applicability": "Applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Computational And Predictive Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"instructionsToUse": "See **Specifications** **Figure 1A** for process to apply codes according to variant type, location and predicted bioinformatic impact.",
"label": "PP3",
"ns": "097",
"originalACMGSummary": "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).\nCaveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
"sepioID": "SEPIO-CG:99035",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0238",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0024",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0019",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not Applicable",
"id": "0025",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"additionalComments": {
"Caveats": [
"Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant."
]
},
"applicability": "Applicable",
"id": "0062",
"instructionsToUse": "",
"specificationType": [
"Gene-specific"
],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.\n\nApply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.\n\nSee Specifications Figure1A and Appendix J for details.",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166134",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166134",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpG--Q"
},
{
"entContent": {
"_uniqueProp": "097_PP2_nuclear_BRCA2",
"additionalComments": "High frequency of benign missense variants.",
"applicability": "Not applicable",
"baseStrength": "Pathogenic",
"defaultStrength": "Pathogenic Supporting",
"evidenceCategory": "Functional Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "PP2",
"ns": "097",
"originalACMGSummary": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.",
"sepioID": "SEPIO-CG:99034",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0237",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0049",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "SEPIO:0000220",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0033",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000330",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0034",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000216",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0061",
"instructionsToUse": "",
"specificationType": [],
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000329",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166125",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166125",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpe--O"
},
{
"entContent": {
"_uniqueProp": "097_BP2_nuclear_BRCA2",
"additionalComments": "Applied only in the context of BS2.",
"applicability": "Not applicable",
"baseStrength": "Benign",
"defaultStrength": "Benign Supporting",
"evidenceCategory": "Allelic Data",
"gene": [
"BRCA2"
],
"geneType": "nuclear",
"label": "BP2",
"ns": "097",
"originalACMGSummary": "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.",
"sepioID": "SEPIO-CG:99044",
"specificationType": [],
"status": {
"Pilot Rules In Prep": {
"completed": true
}
},
"strengthDescriptor": [
{
"applicability": "Not applicable",
"id": "0209",
"instructionsToUse": "",
"status": "approved",
"strength": "Stand Alone",
"strengthSepioID": "SEPIO:0000325",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0207",
"instructionsToUse": "",
"status": "approved",
"strength": "Very Strong",
"strengthSepioID": "",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0068",
"instructionsToUse": "",
"status": "approved",
"strength": "Strong",
"strengthSepioID": "SEPIO:0000328",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0208",
"instructionsToUse": "",
"status": "approved",
"strength": "Moderate",
"strengthSepioID": "SEPIO:0000699",
"text": "",
"type": "EvidenceLineStrength"
},
{
"applicability": "Not applicable",
"id": "0084",
"instructionsToUse": "",
"status": "approved",
"strength": "Supporting",
"strengthSepioID": "SEPIO:0000327",
"text": "",
"type": "EvidenceLineStrength"
}
]
},
"entType": "CriteriaCode",
"ldhId": "1614166120",
"ldhIri": "https://genboree.org/cspec/CriteriaCode/id/1614166120",
"modified": "2023-12-21T20:17:20.267Z",
"modifier": "michaelP",
"rev": "_h6SHxpi--J"
}
],
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0012933",
"lbl": "breast-ovarian cancer, familial, susceptibility to, 2",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/4521"
},
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/9285"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0012933"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/breast_ovarian_cancer_familial_2_2"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/382625"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C2675520"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "https://omim.org/entry/612555"
}
],
"definition": {
"val": "Any hereditary breast ovarian cancer syndrome in which the cause of the disease is a mutation in the BRCA2 gene.",
"xrefs": [
"MONDO:patterns/disease_series_by_gene"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#inferred_rare",
"http://purl.obolibrary.org/obo/mondo#omim_susceptibility",
"http://purl.obolibrary.org/obo/mondo#predisposition",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "BRCA2 hereditary breast ovarian cancer syndrome",
"xrefs": [
"MONDO:design_pattern",
"MONDO:patterns/disease_series_by_gene"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, 2"
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, 2",
"xrefs": [
"MONDO:Lexical",
"OMIM:612555"
]
},
{
"pred": "hasExactSynonym",
"val": "breast-ovarian cancer, familial, susceptibility to, type 2",
"xrefs": [
"MONDORULE:1"
]
},
{
"pred": "hasExactSynonym",
"val": "hereditary breast ovarian cancer syndrome caused by mutation in BRCA2",
"xrefs": [
"MONDO:design_pattern"
]
},
{
"pred": "hasRelatedSynonym",
"synonymType": "http://purl.obolibrary.org/obo/mondo#ABBREVIATION",
"val": "BROVCA2",
"xrefs": [
"MONDO:Lexical"
]
},
{
"pred": "hasRelatedSynonym",
"val": "breast cancer, familial, susceptibility to, 2"
},
{
"pred": "hasRelatedSynonym",
"val": "ovarian cancer, familial, susceptibility to, 2"
},
{
"pred": "hasRelatedSynonym",
"val": "susceptibility to familial breast-ovarian cancer 2"
}
],
"xrefs": [
{
"val": "MEDGEN:382625"
},
{
"val": "OMIM:612555"
},
{
"val": "UMLS:C2675520"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0012933",
"name": "breast-ovarian cancer, familial, susceptibility to, 2"
},
"entId": "MONDO:0012933",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0012933",
"entType": "Disease",
"ldhId": "467873801",
"ldhIri": "https://genboree.org/cspec/Disease/id/467873801",
"modified": "2025-10-07T15:44:52.543Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7Wx7----"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056943391277000,
"agr": "HGNC:1101",
"alias_name": [
"BRCA1/BRCA2-containing complex, subunit 2"
],
"alias_symbol": [
"FAD",
"FAD1",
"BRCC2",
"XRCC11"
],
"ccds_id": [
"CCDS9344"
],
"cosmic": "BRCA2",
"date_approved_reserved": "1994-10-17",
"date_modified": "2021-05-26",
"date_name_changed": "2019-01-22",
"ena": [
"U43746"
],
"ensembl_gene_id": "ENSG00000139618",
"entrez_id": "675",
"gene_group": [
"FA complementation groups"
],
"gene_group_id": [
548
],
"hgnc_id": "HGNC:1101",
"location": "13q13.1",
"location_sortable": "13q13.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"Breast Cancer|http://research.nhgri.nih.gov/bic/",
"Fanconi Anaemia Mutation Database|http://www2.rockefeller.edu/fanconi/",
"BRCA1 database at LOVD-China|http://genomed.org/LOVD/BC/home.php?select_db=BRCA2",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/BRCA2",
"LOVD - Leiden Open Variation Database|http://proteomics.bio21.unimelb.edu.au/lovd/genes/BRCA2",
"Global Variome shared LOVD|https://databases.lovd.nl/shared/genes/FANCD1",
"LRG_293|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_293.xml"
],
"mane_select": [
"ENST00000380152.8",
"NM_000059.4"
],
"mgd_id": [
"MGI:109337"
],
"name": "BRCA2 DNA repair associated",
"omim_id": [
"600185"
],
"orphanet": 119072,
"prev_name": [
"Fanconi anemia, complementation group D1",
"breast cancer 2, early onset",
"breast cancer 2"
],
"prev_symbol": [
"FANCD1",
"FACD",
"FANCD"
],
"pubmed_id": [
8091231,
7581463,
15057823
],
"refseq_accession": [
"NM_000059"
],
"rgd_id": [
"RGD:2219"
],
"status": "Approved",
"symbol": "BRCA2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc001uub.2",
"uniprot_ids": [
"P51587"
],
"uuid": "c1732bf3-cd86-42a2-b8e3-76e8da2d317c",
"vega_id": "OTTHUMG00000017411"
}
},
"entId": "BRCA2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1101",
"entType": "Gene",
"ldhId": "467818963",
"ldhIri": "https://genboree.org/cspec/Gene/id/467818963",
"modified": "2021-10-14T11:36:31.267Z",
"modifier": "genbadmin",
"rev": "_h6SHyDu--O"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "097_nuclear_BRCA2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"adjective": "None",
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0012933",
"preferredTitle": "breast-ovarian cancer, familial, susceptibility to, 2"
}
],
"gene": "BRCA2",
"preferredTranscript": "NM_000059.4"
}
],
"ns": "097",
"references": [],
"rules": {
"mainRules": [
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"label": "Rule1, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=1",
"label": "Rule1, Condition2",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule1"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"label": "Rule4, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule4, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule4"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule6, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule6, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule6"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule7, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule7, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule7, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule7"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule8, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule8, Condition2",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule8, Condition3",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule8"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==1",
"label": "Rule12, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule12, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule12"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=3",
"label": "Rule13, Condition1",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule13"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==2",
"label": "Rule14, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"label": "Rule14, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule14"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": "==1",
"label": "Rule15, Condition1",
"partitionPath": "Pathogenic.Moderate"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=4",
"label": "Rule15, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Likely Pathogenic",
"rule": "Rule15"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": ">=2",
"label": "Rule16, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Benign",
"rule": "Rule16"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BA1"
],
"condition": "==1",
"label": "Rule17, Condition1",
"partitionPath": "Benign.Stand Alone"
}
],
"inference": "Benign",
"rule": "Rule17"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"label": "Rule18, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": "==1",
"label": "Rule18, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule18"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=2",
"label": "Rule19, Condition1",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Very Strong"
},
{
"applicableCriteriaCodes": [
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule19, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule19, Condition1",
"partitionPath": "Pathogenic.Strong"
}
],
"inference": "Pathogenic",
"rule": "Rule19"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule20, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Moderate",
"PS1_Moderate",
"PM3",
"PM5",
"PP1_Moderate",
"PP4_Moderate"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule20, Condition2",
"partitionPath": "Pathogenic.Moderate"
}
],
"inference": "Pathogenic",
"rule": "Rule20"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"PVS1_Strong",
"PS1",
"PS3",
"PS4",
"PM3_Strong",
"PM5_Strong",
"PP1_Strong",
"PP4_Strong"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Pathogenic.Strong"
},
{
"applicableCriteriaCodes": [
"PVS1_Supporting",
"PS1_Supporting",
"PM2_Supporting",
"PM3_Supporting",
"PM5_Supporting",
"PP1",
"PP3",
"PP4"
],
"condition": ">=2",
"getpartitionPath": "",
"label": "Rule21, Condition2",
"partitionPath": "Pathogenic.Supporting"
}
],
"inference": "Pathogenic",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule21, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==2",
"getpartitionPath": "",
"label": "Rule21, Condition2",
"partitionPath": "Benign.Moderate"
}
],
"inference": "Benign",
"rule": "Rule21"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition2",
"partitionPath": "Benign.Moderate"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule22, Condition3",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Benign",
"rule": "Rule22"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule23, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=3",
"getpartitionPath": "",
"label": "Rule23, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Benign",
"rule": "Rule23"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BP1_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule24, Condition1",
"partitionPath": "Benign.Strong"
}
],
"inference": "Likely Benign",
"rule": "Rule24"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS1",
"BS2",
"BS3",
"BS4",
"BP1_Strong",
"BP5_Strong",
"BP7_Strong"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition1",
"partitionPath": "Benign.Strong"
},
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule22, Condition2",
"partitionPath": "Benign.Moderate"
}
],
"inference": "Likely Benign",
"rule": "Rule22"
},
{
"conditions": [
{
"applicableCriteriaCodes": [
"BS2_Moderate",
"BS4_Moderate",
"BP5_Moderate"
],
"condition": "==1",
"getpartitionPath": "",
"label": "Rule23, Condition1",
"partitionPath": "Benign.Moderate"
},
{
"applicableCriteriaCodes": [
"BS1_Supporting",
"BS2_Supporting",
"BS4_Supporting",
"BP4",
"BP5",
"BP7"
],
"condition": ">=1",
"getpartitionPath": "",
"label": "Rule23, Condition2",
"partitionPath": "Benign.Supporting"
}
],
"inference": "Likely Benign",
"rule": "Rule23"
}
]
}
},
"entType": "RuleSet",
"ldhId": "1535438847",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535438847",
"modified": "2023-12-21T20:17:20.160Z",
"modifier": "michaelP",
"rev": "_h6SHyTK--I"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"abbreviation": "BRCA1/BRCA2",
"approval": {
"step1": {
"approvalDate": "2020-12-12T00:00:00.000Z",
"approved": true
},
"step2": {
"approvalDate": "2021-12-13T00:00:00.000Z",
"approved": true
},
"step3": {
"approvalDate": "2023-04-28T00:00:00.000Z",
"approved": true
},
"step4": {
"approvalDate": "2023-08-08T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "ENIGMA BRCA1 and BRCA2",
"shortBaseName": "BRCA1/BRCA2",
"shortTitle": "ENIGMA BRCA1 and BRCA2 VCEP",
"title": "ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50087",
"entIri": "http://clinicalgenome.org/affiliation/50087",
"entType": "Organization",
"ldhId": "639508895",
"ldhIri": "https://genboree.org/cspec/Organization/id/639508895",
"modified": "2023-08-08T12:53:03.856Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--e"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535438831",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535438831",
"modified": "2023-12-21T20:17:20.109Z",
"modifier": "michaelP",
"rev": "_h6SHyk---H"
},
{
"entContent": {
"description": "",
"namespace": "GN098",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T02:36:26.682Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:05.858Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:02.875Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"098"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNI3 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN098",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005045",
"lbl": "hypertrophic cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5962"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypertrophic_cardiomyopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_hypertrophic_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020871"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1830681485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2881"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002312"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/233873004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_11984"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34449"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000538"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#narrowMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#relatedMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
}
],
"definition": {
"val": "A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.",
"xrefs": [
"NCIT:C34449"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hypertrophic cardiomyopathy",
"xrefs": [
"DOID:11984",
"NCIT:C34449",
"icd11.foundation:1830681485"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic obstructive cardiomyopathy",
"xrefs": [
"DOID:11984"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic subaortic stenosis"
},
{
"pred": "hasExactSynonym",
"val": "obstructive hypertrophic cardiomyopathy"
},
{
"pred": "hasNarrowSynonym",
"val": "familial hypertrophic cardiomyopathy"
},
{
"pred": "hasRelatedSynonym",
"val": "HCM - hypertrophic cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:11984"
},
{
"val": "EFO:0000538"
},
{
"val": "HP:0001639"
},
{
"val": "ICD10CM:I42.1"
},
{
"val": "ICD10CM:I42.2"
},
{
"val": "ICD9:425.1"
},
{
"val": "ICD9:425.11"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2881"
},
{
"val": "MESH:D002312"
},
{
"val": "MedDRA:10020871"
},
{
"val": "NANDO:1200286"
},
{
"val": "NANDO:1200288"
},
{
"val": "NANDO:2100054"
},
{
"val": "NANDO:2200229"
},
{
"val": "NANDO:2201042"
},
{
"val": "NCIT:C34449"
},
{
"val": "Orphanet:217569"
},
{
"val": "SCTID:233873004"
},
{
"val": "UMLS:C0007194"
},
{
"val": "icd11.foundation:1830681485"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005045",
"name": "hypertrophic cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005045",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005045",
"entType": "Disease",
"ldhId": "135641999",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641999",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9FG---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056965392498700,
"agr": "HGNC:11947",
"alias_symbol": [
"TNNC1",
"CMH7"
],
"ccds_id": [
"CCDS42628"
],
"date_approved_reserved": "1989-12-11",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-16",
"ena": [
"M64247"
],
"ensembl_gene_id": "ENSG00000129991",
"entrez_id": "7137",
"gene_group": [
"Troponin complex subunits"
],
"gene_group_id": [
1219
],
"hgnc_id": "HGNC:11947",
"location": "19q13.42",
"location_sortable": "19q13.42",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"FHC Mutation Database|http://www.angis.org.au/Databases/Heart/heartbreak.html",
"LRG_432|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_432.xml"
],
"mane_select": [
"ENST00000344887.10",
"NM_000363.5"
],
"mgd_id": [
"MGI:98783"
],
"name": "troponin I3, cardiac type",
"omim_id": [
"191044"
],
"orphanet": 120184,
"prev_name": [
"cardiomyopathy, dilated 2A (autosomal recessive)",
"troponin I type 3 (cardiac)",
"troponin I type 3"
],
"prev_symbol": [
"CMD2A"
],
"pubmed_id": [
9605869,
9241277,
10806205
],
"refseq_accession": [
"NM_000363"
],
"rgd_id": [
"RGD:62052"
],
"status": "Approved",
"symbol": "TNNI3",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002qjg.5",
"uniprot_ids": [
"P19429"
],
"uuid": "3e52a91d-b487-48d6-9ac3-09b4ed82eaac",
"vega_id": "OTTHUMG00000180589"
}
},
"entId": "TNNI3",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11947",
"entType": "Gene",
"ldhId": "467860673",
"ldhIri": "https://genboree.org/cspec/Gene/id/467860673",
"modified": "2021-10-14T11:37:12.512Z",
"modifier": "genbadmin",
"rev": "_h6SH0QK--D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "098_nuclear_TNNI3",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0005045",
"preferredTitle": "hypertrophic cardiomyopathy"
}
],
"gene": "TNNI3",
"preferredTranscript": "NM_000363.5"
}
],
"ns": "098",
"references": []
},
"entType": "RuleSet",
"ldhId": "1535821579",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535821579",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--S"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2017-04-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cardiomyopathy",
"shortBaseName": "CMP",
"shortTitle": "Cardiomyopathy VCEP",
"title": "Cardiomyopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50002",
"entIri": "http://clinicalgenome.org/affiliation/50002",
"entType": "Organization",
"ldhId": "135637627",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637627",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--U"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535821566",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535821566",
"modified": "2024-03-25T21:15:06.031Z",
"modifier": "makelly2",
"rev": "_h6SHykK--P"
},
{
"entContent": {
"description": "",
"namespace": "GN099",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:19:18.304Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:23.858Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:12.768Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"099"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNT2 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN099",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005021",
"lbl": "dilated cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005021"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/dilated_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10056370"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1916294688"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2880"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002311"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/195021004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007193"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.0"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_12930"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C84673"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000407"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217604"
}
],
"definition": {
"val": "Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.",
"xrefs": [
"NCIT:P378"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#gard_rare",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "dilated cardiomyopathy",
"xrefs": [
"DOID:12930",
"ICD10CM:I42.0",
"NCIT:C84673",
"Orphanet:217604",
"icd11.foundation:1916294688"
]
},
{
"pred": "hasRelatedSynonym",
"val": "congestive cardiomyopathy",
"xrefs": [
"DOID:12930"
]
},
{
"pred": "hasRelatedSynonym",
"val": "familial dilated cardiomyopathy",
"xrefs": [
"DOID:12930",
"MESH:C536231"
]
},
{
"pred": "hasRelatedSynonym",
"val": "idiopathic dilation cardiomyopathy",
"xrefs": [
"DOID:12930",
"MESH:C536277"
]
},
{
"pred": "hasRelatedSynonym",
"val": "primary dilated cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:12930"
},
{
"val": "EFO:0000407"
},
{
"val": "GARD:221"
},
{
"val": "HP:0001644"
},
{
"val": "ICD10CM:I42.0"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2880"
},
{
"val": "MESH:D002311"
},
{
"val": "MedDRA:10056370"
},
{
"val": "NANDO:2100057"
},
{
"val": "NANDO:2200232"
},
{
"val": "NCIT:C84673"
},
{
"val": "Orphanet:217604"
},
{
"val": "SCTID:195021004"
},
{
"val": "UMLS:C0007193"
},
{
"val": "icd11.foundation:1916294688"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005021",
"name": "dilated cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005021",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005021",
"entType": "Disease",
"ldhId": "135641998",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641998",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9_S---"
},
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005045",
"lbl": "hypertrophic cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5962"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypertrophic_cardiomyopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_hypertrophic_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020871"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1830681485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2881"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002312"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/233873004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_11984"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34449"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000538"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#narrowMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#relatedMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
}
],
"definition": {
"val": "A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.",
"xrefs": [
"NCIT:C34449"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hypertrophic cardiomyopathy",
"xrefs": [
"DOID:11984",
"NCIT:C34449",
"icd11.foundation:1830681485"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic obstructive cardiomyopathy",
"xrefs": [
"DOID:11984"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic subaortic stenosis"
},
{
"pred": "hasExactSynonym",
"val": "obstructive hypertrophic cardiomyopathy"
},
{
"pred": "hasNarrowSynonym",
"val": "familial hypertrophic cardiomyopathy"
},
{
"pred": "hasRelatedSynonym",
"val": "HCM - hypertrophic cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:11984"
},
{
"val": "EFO:0000538"
},
{
"val": "HP:0001639"
},
{
"val": "ICD10CM:I42.1"
},
{
"val": "ICD10CM:I42.2"
},
{
"val": "ICD9:425.1"
},
{
"val": "ICD9:425.11"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2881"
},
{
"val": "MESH:D002312"
},
{
"val": "MedDRA:10020871"
},
{
"val": "NANDO:1200286"
},
{
"val": "NANDO:1200288"
},
{
"val": "NANDO:2100054"
},
{
"val": "NANDO:2200229"
},
{
"val": "NANDO:2201042"
},
{
"val": "NCIT:C34449"
},
{
"val": "Orphanet:217569"
},
{
"val": "SCTID:233873004"
},
{
"val": "UMLS:C0007194"
},
{
"val": "icd11.foundation:1830681485"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005045",
"name": "hypertrophic cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005045",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005045",
"entType": "Disease",
"ldhId": "135641999",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641999",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9FG---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056965394595800,
"agr": "HGNC:11949",
"alias_symbol": [
"CMPD2"
],
"ccds_id": [
"CCDS30969",
"CCDS73003",
"CCDS73002",
"CCDS30968",
"CCDS60390"
],
"date_approved_reserved": "1993-09-27",
"date_modified": "2021-05-26",
"date_name_changed": "2016-02-16",
"ena": [
"X74819"
],
"ensembl_gene_id": "ENSG00000118194",
"entrez_id": "7139",
"gene_group": [
"Troponin complex subunits"
],
"gene_group_id": [
1219
],
"hgnc_id": "HGNC:11949",
"location": "1q32.1",
"location_sortable": "01q32.1",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"FHC Mutation Database|http://www.angis.org.au/Databases/Heart/heartbreak.html",
"LRG_431|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_431.xml"
],
"mane_select": [
"ENST00000656932.1",
"NM_001276345.2"
],
"mgd_id": [
"MGI:104597"
],
"name": "troponin T2, cardiac type",
"omim_id": [
"191045"
],
"orphanet": 120190,
"prev_name": [
"cardiomyopathy, hypertrophic 2",
"cardiomyopathy, dilated 1D (autosomal dominant)",
"troponin T type 2 (cardiac)"
],
"prev_symbol": [
"CMH2",
"CMD1D"
],
"pubmed_id": [
8088824,
8205619,
9482583
],
"refseq_accession": [
"NM_000364"
],
"rgd_id": [
"RGD:3882"
],
"status": "Approved",
"symbol": "TNNT2",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc057ohe.1",
"uniprot_ids": [
"P45379"
],
"uuid": "8a849b7e-01cf-4669-9d3c-856dc510d100",
"vega_id": "OTTHUMG00000035733"
}
},
"entId": "TNNT2",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11949",
"entType": "Gene",
"ldhId": "467860676",
"ldhIri": "https://genboree.org/cspec/Gene/id/467860676",
"modified": "2021-10-14T11:37:12.512Z",
"modifier": "genbadmin",
"rev": "_h6SH0R----"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "099_nuclear_TNNT2",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0005045",
"preferredTitle": "hypertrophic cardiomyopathy"
},
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0005021",
"preferredTitle": "dilated cardiomyopathy"
}
],
"gene": "TNNT2",
"preferredTranscript": "NM_001276345.2"
}
],
"ns": "099",
"references": []
},
"entType": "RuleSet",
"ldhId": "1535826201",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535826201",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTW--X"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2017-04-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cardiomyopathy",
"shortBaseName": "CMP",
"shortTitle": "Cardiomyopathy VCEP",
"title": "Cardiomyopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50002",
"entIri": "http://clinicalgenome.org/affiliation/50002",
"entType": "Organization",
"ldhId": "135637627",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637627",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--U"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535826188",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535826188",
"modified": "2024-03-25T21:15:24.008Z",
"modifier": "makelly2",
"rev": "_h6SHykG--N"
},
{
"entContent": {
"description": "",
"namespace": "GN100",
"releaseNotes": "",
"shortTitle": "Cardiomyopathy Specification",
"specificationSource": "",
"states": [
{
"current": false,
"event": {
"name": "cspec-created",
"prevState": "START",
"timeStamp": "2022-12-05T03:24:58.208Z"
},
"name": "Pilot Rules In Prep"
},
{
"current": true,
"event": {
"name": "pilot-rules-submitted",
"prevState": "Pilot Rules In Prep",
"timeStamp": "2024-03-25T21:15:41.902Z"
},
"name": "Pilot Rules Submitted"
},
{
"current": false,
"event": {
"name": "pilot-rules-reviewed",
"prevState": "Pilot Rules Submitted",
"timeStamp": "2024-02-05T15:44:22.430Z"
},
"name": "Pilot Rules In Prep"
}
],
"tagNameSpaces": [
"100"
],
"title": "ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TPM1 Version 1.0.0",
"version": "1.0.0",
"versioned": true
},
"entId": "GN100",
"entType": "SequenceVariantInterpretation",
"ld": {
"Disease": [
{
"entContent": {
"MONDO": {
"id": "http://purl.obolibrary.org/obo/MONDO_0005045",
"lbl": "hypertrophic cardiomyopathy",
"meta": {
"basicPropertyValues": [
{
"pred": "http://purl.obolibrary.org/obo/IAO_0000233",
"val": "https://github.com/monarch-initiative/mondo/issues/5962"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://search.clinicalgenome.org/kb/conditions/MONDO:0005045"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/hypertrophic_cardiomyopathy"
},
{
"pred": "http://purl.obolibrary.org/obo/mondo#curated_content_resource",
"val": "https://www.malacards.org/card/rare_hypertrophic_cardiomyopathy"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#closeMatch",
"val": "http://identifiers.org/meddra/10020871"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://id.who.int/icd/entity/1830681485"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/medgen/2881"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/mesh/D002312"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://identifiers.org/snomedct/233873004"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://linkedlifedata.com/resource/umls/id/C0007194"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/DOID_11984"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://purl.obolibrary.org/obo/NCIT_C34449"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.ebi.ac.uk/efo/EFO_0000538"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#exactMatch",
"val": "http://www.orpha.net/ORDO/Orphanet_217569"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#narrowMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.1"
},
{
"pred": "http://www.w3.org/2004/02/skos/core#relatedMatch",
"val": "http://purl.bioontology.org/ontology/ICD10CM/I42.2"
}
],
"definition": {
"val": "A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.",
"xrefs": [
"NCIT:C34449"
]
},
"subsets": [
"http://purl.obolibrary.org/obo/mondo#clingen",
"http://purl.obolibrary.org/obo/mondo#disease_grouping",
"http://purl.obolibrary.org/obo/mondo#nord_rare",
"http://purl.obolibrary.org/obo/mondo#ordo_group_of_disorders",
"http://purl.obolibrary.org/obo/mondo#otar",
"http://purl.obolibrary.org/obo/mondo#rare"
],
"synonyms": [
{
"pred": "hasExactSynonym",
"val": "hypertrophic cardiomyopathy",
"xrefs": [
"DOID:11984",
"NCIT:C34449",
"icd11.foundation:1830681485"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic obstructive cardiomyopathy",
"xrefs": [
"DOID:11984"
]
},
{
"pred": "hasExactSynonym",
"val": "hypertrophic subaortic stenosis"
},
{
"pred": "hasExactSynonym",
"val": "obstructive hypertrophic cardiomyopathy"
},
{
"pred": "hasNarrowSynonym",
"val": "familial hypertrophic cardiomyopathy"
},
{
"pred": "hasRelatedSynonym",
"val": "HCM - hypertrophic cardiomyopathy"
}
],
"xrefs": [
{
"val": "DOID:11984"
},
{
"val": "EFO:0000538"
},
{
"val": "HP:0001639"
},
{
"val": "ICD10CM:I42.1"
},
{
"val": "ICD10CM:I42.2"
},
{
"val": "ICD9:425.1"
},
{
"val": "ICD9:425.11"
},
{
"val": "ICD9:425.4"
},
{
"val": "MEDGEN:2881"
},
{
"val": "MESH:D002312"
},
{
"val": "MedDRA:10020871"
},
{
"val": "NANDO:1200286"
},
{
"val": "NANDO:1200288"
},
{
"val": "NANDO:2100054"
},
{
"val": "NANDO:2200229"
},
{
"val": "NANDO:2201042"
},
{
"val": "NCIT:C34449"
},
{
"val": "Orphanet:217569"
},
{
"val": "SCTID:233873004"
},
{
"val": "UMLS:C0007194"
},
{
"val": "icd11.foundation:1830681485"
}
]
},
"type": "CLASS"
},
"MONDOID": "MONDO:0005045",
"name": "hypertrophic cardiomyopathy",
"preferredModeOfInheritance": {
"inheritance": "Autosomal dominant inheritance",
"sepioID": "HP:0000006"
}
},
"entId": "MONDO:0005045",
"entIri": "http://purl.obolibrary.org/obo/MONDO_0005045",
"entType": "Disease",
"ldhId": "135641999",
"ldhIri": "https://genboree.org/cspec/Disease/id/135641999",
"modified": "2025-10-07T15:42:52.850Z",
"modifier": "cspecAdministrator",
"rev": "_kZ7U9FG---"
}
],
"Gene": [
{
"entContent": {
"HGNC": {
"_version_": 1704056965477433300,
"agr": "HGNC:12010",
"ccds_id": [
"CCDS10181",
"CCDS86459",
"CCDS58369",
"CCDS81891",
"CCDS81892",
"CCDS81894",
"CCDS45273",
"CCDS58368",
"CCDS32262",
"CCDS32263",
"CCDS32264"
],
"date_approved_reserved": "1991-07-18",
"date_modified": "2021-05-26",
"date_name_changed": "2017-05-24",
"ena": [
"AB209041"
],
"ensembl_gene_id": "ENSG00000140416",
"entrez_id": "7168",
"gene_group": [
"Tropomyosins"
],
"gene_group_id": [
777
],
"hgnc_id": "HGNC:12010",
"location": "15q22.2",
"location_sortable": "15q22.2",
"locus_group": "protein-coding gene",
"locus_type": "gene with protein product",
"lsdb": [
"FHC Mutation Database|http://www.angis.org.au/Databases/Heart/heartbreak.html",
"LRG_387|http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_387.xml"
],
"mane_select": [
"ENST00000403994.9",
"NM_001018005.2"
],
"mgd_id": [
"MGI:98809"
],
"name": "tropomyosin 1",
"omim_id": [
"191010"
],
"orphanet": 120220,
"prev_name": [
"chromosome 15 open reading frame 13",
"cardiomyopathy, hypertrophic 3",
"tropomyosin 1 (alpha)"
],
"prev_symbol": [
"C15orf13",
"CMH3"
],
"pubmed_id": [
10343096,
8205619,
25369766
],
"refseq_accession": [
"NM_001018004"
],
"rgd_id": [
"RGD:3898"
],
"status": "Approved",
"symbol": "TPM1",
"symbol_report_tag": [
"Stable symbol"
],
"ucsc_id": "uc002alh.4",
"uniprot_ids": [
"P09493"
],
"uuid": "e98082bf-d830-41f0-b821-e63016aacb34",
"vega_id": "OTTHUMG00000132803"
}
},
"entId": "TPM1",
"entIri": "https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12010",
"entType": "Gene",
"ldhId": "467860829",
"ldhIri": "https://genboree.org/cspec/Gene/id/467860829",
"modified": "2021-10-14T11:37:12.594Z",
"modifier": "genbadmin",
"rev": "_h6SH0R---D"
}
],
"RuleSet": [
{
"entContent": {
"_uniqueProp": "100_nuclear_TPM1",
"geneType": "nuclear",
"genes": [
{
"diseases": [
{
"preferredModeOfInheritance": "Autosomal dominant inheritance",
"preferredMondoId": "MONDO:0005045",
"preferredTitle": "hypertrophic cardiomyopathy"
}
],
"gene": "TPM1",
"preferredTranscript": "NM_001018005.2"
}
],
"ns": "100",
"references": []
},
"entType": "RuleSet",
"ldhId": "1535827410",
"ldhIri": "https://genboree.org/cspec/RuleSet/id/1535827410",
"modified": "2023-01-27T21:39:11.248Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyTO--U"
}
]
},
"ldFor": {
"Organization": [
{
"entContent": {
"approval": {
"step1": {
"approved": true
},
"step2": {
"approved": true
},
"step3": {
"approved": true
},
"step4": {
"approvalDate": "2017-04-29T00:00:00.000Z",
"approved": true
}
},
"curationActivity": "Variant Pathogenicity",
"fullBaseName": "Cardiomyopathy",
"shortBaseName": "CMP",
"shortTitle": "Cardiomyopathy VCEP",
"title": "Cardiomyopathy Variant Curation Expert Panel",
"type": "Variant Curation Expert Panel"
},
"entId": "50002",
"entIri": "http://clinicalgenome.org/affiliation/50002",
"entType": "Organization",
"ldhId": "135637627",
"ldhIri": "https://genboree.org/cspec/Organization/id/135637627",
"modified": "2023-04-07T14:55:06.014Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHyEy--U"
}
],
"SequenceVariantInterpretation": [
{
"entContent": {
"approvedOn": "03-05-2015",
"description": "ACMG ISV guidelines 2015",
"namespace": "GN001",
"notes": "",
"references": [
{
"source": "PubMed",
"url": "https://pubmed.ncbi.nlm.nih.gov/25741868"
}
],
"shortTitle": "ACMG 2015-Guidelines",
"specificationSource": "https://www.acmg.net/docs/Standards_Guidelines_for_the_Interpretation_of_Sequence_Variants.pdf",
"tagNameSpaces": [
"001"
],
"title": "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology",
"version": "1.0.0"
},
"entId": "GN001",
"entType": "SequenceVariantInterpretation",
"ldhId": "135637585",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637585",
"modified": "2022-08-18T15:51:43.074Z",
"modifier": "cspecAdministrator",
"rev": "_h6SHykG---"
}
]
},
"ldhId": "1535827397",
"ldhIri": "https://genboree.org/cspec/SequenceVariantInterpretation/id/1535827397",
"modified": "2024-03-25T21:15:42.007Z",
"modifier": "makelly2",
"rev": "_h6SHykK--Q"
}
],
"metadata": {
"rendered": {
"by": "https://genboree.org/cspec/srvc",
"when": "2026-05-04T12:32:17.316Z"
}
},
"status": {
"code": 200,
"name": "OK"
}
}