Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).
For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.
The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.
MYH7-associated inherited cardiomyopathies - adapted from ACMG/AMP
Allele frequency is >= 0.1% based on the filtering allele frequency (FAF) in ExAC BA1
Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information BS1
Variant identified in >=2 probands with consistent phenotypes PS4-Supporting
Variant identified in >=6 probands with consistent phenotypes PS4-Moderate
Absent/extremely rare (<0.004%) from large population studies. PM2
Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls -OR- Variant identified in ≥15 probands with consistent phenotypes PS4
Multiple lines of computational evidence suggest no impact on gene or gene product BP4
A silent variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site -AND- the nucleotide is not highly conserved BP7
Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP3
Null Variant in gene with evidence supporting LOF as disease mechanism PVS1-Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before PM5
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants PM4
Same amino acid change as an established pathogenic variant PS1
Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing BS3
Located in a mutational hot spot and/or critical and well-established functional domain. PM1
Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product PS3
Non-segregation in affected members of a family BS4
Variant segragates in >=3 meioses PP1
Variant segragates in >=5 meioses PP1-Moderate
Variant segregates with >= 7 meioses PP1-Strong
Confirmed de novo without confirmation of paternity PM6
De novo (paternity confirmed) in a patient with disease and no family history PS2
Observed as comp het (in trans) or double het in genes with overlapping function (e.g. sarcomere genes) without increased disease severity -OR- Observed in cis with a pathogenic variant in any inheritance pattern BP2
Variant found in a case with an alternate molecular basis for disease BP5