{ "data": { "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": [ 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