{ "@context": "https://genboree.org/cspec/api/context/SequenceVariantInterpretation", "@id": "https://genboree.org/cspec/api/SequenceVariantInterpretation/id/GN016", "@type": "Criteria Specification", "affiliation": { "@id": "https://genboree.org/cspec/api/Organization/id/50022", "@type": "Organization", "label": "Rett and Angelman-like Disorders Variant Curation Expert Panel", "url": "http://clinicalgenome.org/affiliation/50022" }, "assertionMethod": { "@id": "_:am1", "@type": "AssertionMethod", "url": "https://genboree.org/cspec/SequenceVariantInterpretation/id/135637589" }, "cspecStatus": "Released", "currentStatus": "Released", "label": "ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2", "lastUpdated": "2021-12-31T00:00:00.000Z", "legacy": true, "legacyReplaced": true, "ruleSets": [ { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641458", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433286/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433285/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638435/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638434/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638424/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638423/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "In-frame deletions/insertions in a repetitive region without a known function.", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638420/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638418/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638417/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638412/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638427/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638416/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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. ", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638414/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638413/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "BS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638433/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638431/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638428/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638425/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638415/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638411/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638436/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638429/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638426/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "PP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638422/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638421/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638432/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638430/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638419/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=CDKL5", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0100039", "@type": "Disease", "label": "MONDO:0100039" } ], "label": "CDKL5" } ] }, { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641459", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433313/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638453/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638448/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638447/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638444/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638438/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638456/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638443/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638442/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638440/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638439/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "BS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638462/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638460/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638457/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638446/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638445/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433312/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638451/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638450/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638449/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638441/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638437/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (Forkhead: aa 181-275).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638461/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638459/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638458/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638455/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638454/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638452/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "PP1" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=FOXG1", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0100040", "@type": "Disease", "label": "MONDO:0100040" } ], "label": "FOXG1" } ] }, { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641460", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638481/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638477/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638475/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "In-frame deletions/insertions in a repetitive region without a known function.", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638471/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638465/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "BS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638464/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433339/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638484/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638480/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638476/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638472/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638469/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638466/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638488/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638482/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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)", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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)", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638478/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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", "label": "Supporting" } ], "label": "PP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638468/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433340/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638487/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638486/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638483/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638479/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638474/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638473/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638470/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638467/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638463/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638485/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=MECP2", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0010726", "@type": "Disease", "label": "MONDO:0010726" } ], "label": "MECP2" } ] }, { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641461", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638508/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638507/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638500/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433367/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638513/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638511/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638510/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638506/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638505/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638502/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638499/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638498/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638491/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "BS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638504/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "PP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638503/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638495/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638509/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638497/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433366/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638514/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638512/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638501/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "In-frame deletions/insertions in a repetitive region without a known function.", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638496/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638494/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638493/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638492/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638490/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638489/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=SLC9A6", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0010278", "@type": "Disease", "label": "MONDO:0010278" } ], "label": "SLC9A6" } ] }, { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641462", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433394/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638516/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638515/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638537/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638535/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638534/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638531/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433393/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638536/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638530/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "PP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638521/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638519/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638518/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* (basic Helix-Loop-Helix domain (bHLH): aa 564-617).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638539/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638533/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Variant found in a case with an alternate molecular basis for disease.\n* Do not apply for any gene if variant is de novo.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638532/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638525/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638524/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638523/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638540/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638538/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638529/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638528/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638527/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "In-frame deletions/insertions in a repetitive region without a known function.", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638526/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638522/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638520/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638517/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "BS2" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=TCF4", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0012589", "@type": "Disease", "label": "MONDO:0012589" } ], "label": "TCF4" } ] }, { "@id": "https://genboree.org/cspec/api/RuleSet/id/135641463", "@type": "RuleSet", "criteriaCodes": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638550/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549", "@type": "CriteriaCode", "description": "Assumed de novo, but without confirmation of paternity and maternity.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Confirmed de novo without confirmation of paternity and maternity.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638549/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638543/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Observed in the heterozygous/hemizygous state in a healthy adult.\n* 2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),", "label": "Supporting" } ], "label": "BS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542", "@type": "CriteriaCode", "description": "For recessive disorders, detected in trans with a pathogenic variant\nNote: This requires testing of parents (or offspring) to determine phase.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638542/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433420/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "BP6" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565", "@type": "CriteriaCode", "description": "Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Located in a mutational hot spot and/or critical and well-established functional domain.\n* 3’ cysteine binding site: aa 820.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638565/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638563/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP7" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561", "@type": "CriteriaCode", "description": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638561/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638556/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Supporting" } ], "label": "PP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638555/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "BP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638554/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "PS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "De novo (maternity and paternity confirmed) in a patient with the disease and no family history.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638552/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PS2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421", "@type": "CriteriaCode", "description": "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Supporting" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/638433421/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "label": "Moderate" } ], "label": "PP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560", "@type": "CriteriaCode", "description": "Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638560/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BA1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559", "@type": "CriteriaCode", "description": "Variant found in a case with an alternate molecular basis for disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Variant found in a case with an alternate molecular basis for disease.\n* ≥3 cases with alternate molecular basis for disease.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638559/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 5+ observations.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* 3-4 observations.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638557/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.\n* Use for 2nd independent occurrence.", "label": "Supporting" } ], "label": "PS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553", "@type": "CriteriaCode", "description": "In frame-deletions/insertions in a repetitive region without a known function.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638553/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "description": "In-frame deletions/insertions in a repetitive region without a known function.", "label": "Supporting" } ], "label": "BP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638546/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "PM5" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638566/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "Absent/rare from controls in an ethnically-matched cohort population sample.\n* Use if absent, zero observations in control databases.", "label": "Supporting" } ], "label": "PM2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638558/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not Applicable for this VCEP", "label": "Supporting" } ], "label": "PVS1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638548/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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.", "label": "Supporting" } ], "label": "BS4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545", "@type": "CriteriaCode", "description": "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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).", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638545/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544", "@type": "CriteriaCode", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544/str/Moderate", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638544/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable as originally described", "description": "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).", "label": "Supporting" } ], "label": "PM4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564", "@type": "CriteriaCode", "description": "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638564/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "Phenotype specific for disease with single genetic etiology.\n* See gene specific clinical phenotype guidelines.", "label": "Supporting" } ], "label": "PP4" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638562/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "* 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).", "label": "Supporting" } ], "label": "PP3" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551", "@type": "CriteriaCode", "description": "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.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638551/str/Supporting", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Supporting" } ], "label": "BP2" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547", "@type": "CriteriaCode", "description": "Missense variant in a gene for which primarily truncating variants are known to cause disease.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547/str/Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638547/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BP1" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541", "@type": "CriteriaCode", "description": "Allele frequency is greater than expected for disorder.", "evidenceStrengths": [ { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541/str/Stand%20Alone", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Stand Alone" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541/str/Very%20Strong", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Very Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541/str/Strong", "@type": "EvidenceStrength", "applicability": "Applicable with VCEP specification", "description": "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.", "label": "Strong" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541/str/Moderate", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Moderate" }, { "@id": "https://genboree.org/cspec/api/CriteriaCode/id/135638541/str/Supporting", "@type": "EvidenceStrength", "applicability": "Not applicable", "label": "Supporting" } ], "label": "BS1" } ], "genes": [ { "@id": "https://www.genenames.org/tools/search/#!/?query=UBE3A", "@type": "Gene", "diseases": [ { "@id": "http://purl.obolibrary.org/obo/MONDO_0007113", "@type": "Disease", "label": "MONDO:0007113" } ], "label": "UBE3A" } ] } ], "version": "2.0.0" }