Evidence Repository - Clinical Genome Resources

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.

ACMG2015-Guidelines

Link to Guideline JSON-LD document

Benign

Pathogenic

Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium BA1

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 BS2

Allele frequency is greater than expected for disorder BS1

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium PM2

Prevalence in affecteds statistically increased over controls PS4

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) BP4

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 BP7

In-frame deletions/insertions in a repetitive region without a known function BP3

Missense in gene where only truncating cause disease BP1

Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP3

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

Predicted nullvariant in a gene where LOF is a known mechanism of disease PVS1

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing BS3

Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP2

Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation PM1

Well-established functional studies show a deleterious effect PS3

Lack of segregation in affected members of a family BS4

Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease PP1

Assumed de novo, but without confirmation of paternity and maternity PM6

De novo (paternity and maternity confirmed) PS2

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 BP2

For recessive disorders, detected in trans with a pathogenic variant PM3

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation BP6

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation PP5

Variant found in a case with an alternate molecular basis for disease BP5

Patients phenotype or family history is highly specific for a disease with a single genetic etiology PP4

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