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
Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium BA1
Allele frequency is greater than expected for disorder BS1
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
BS2 downgraded in strength to supporting BS2-Supporting
BS1 downgraded in strength to supporting BS1-Supporting
PM2 downgraded in strength to Supporting PM2-Supporting
PS4 downgraded in strength to Supporting PS4-Supporting
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium PM2
PS4 downgraded in strength to Moderate PS4-Moderate
PM2 upgraded in strength to Strong PM2-Strong
Prevalence in affecteds statistically increased over controls PS4
PM2 upgraded in strength to Very Strong PM2-Very Strong
PS4 upgraded in strength to Very Strong PS4-Very Strong
BP1 upgraded in strength to strong BP1-Strong
BP7 upgraded in strength to strong BP7-Strong
BP3 upgraded in strength to strong BP3-Strong
BP4 upgraded in strength to strong BP4-Strong
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 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
PM4 downgraded in strength to Supporting PM4-Supporting
Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP3
PVS1 downgraded in strength to Supporting PVS1-Supporting
PM5 downgraded in strength to Supporting PM5-Supporting
PS1 downgraded in strength to Supporting PS1-Supporting
PVS1 downgraded in strength to Moderate PVS1-Moderate
PS1 downgraded in strength to Moderate PS1-Moderate
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants PM4
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before PM5
PP3 upgraded in strength to Moderate PP3-Moderate
PP3 upgraded in strength to Strong PP3-Strong
PM4 upgraded in strength to Strong PM4-Strong
PVS1 downgraded in strength to Strong PVS1-Strong
Same amino acid change as an established pathogenic variant PS1
PM5 upgraded in strength to Strong PM5-Strong
Predicted nullvariant in a gene where LOF is a known mechanism of disease PVS1
PP3 upgraded in strength to Very Strong PP3-Very Strong
PS1 upgraded in strength to Very Strong PS1-Very Strong
PM4 upgraded in strength to Very Strong PM4-Very Strong
PM5 upgraded in strength to Very Strong PM5-Very Strong
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing BS3
BS3 downgraded in strength to supporting BS3-Supporting
PM1 downgraded in strength to Supporting PM1-Supporting
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
PS3 downgraded in strength to Supporting PS3-Supporting
PS3 downgraded in strength to Moderate PS3-Moderate
PP2 upgraded in strength to Moderate PP2-Moderate
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
PP2 upgraded in strength to Strong PP2-Strong
Well-established functional studies show a deleterious effect PS3
PM1 upgraded in strength to Strong PM1-Strong
PM1 upgraded in strength to Very Strong PM1-Very Strong
PP2 upgraded in strength to Very Strong PP2-Very Strong
PS3 upgraded in strength to Very Strong PS3-Very Strong
Lack of segregation in affected members of a family BS4
BS4 downgraded in strength to supporting BS4-Supporting
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease PP1
PP1 upgraded in strength to Moderate PP1-Moderate
PP1 upgraded in strength to Strong PP1-Strong
PP1 upgraded in strength to Very Strong PP1-Very Strong
PS2 downgraded in strength to Supporting PS2-Supporting
PM6 downgraded in strength to Supporting PM6-Supporting
Assumed de novo, but without confirmation of paternity and maternity PM6
PS2 downgraded in strength to Moderate PS2-Moderate
PM6 upgraded in strength to Strong PM6-Strong
De novo (paternity and maternity confirmed) PS2
PM6 upgraded in strength to Very Strong PM6-Very Strong
PS2 upgraded in strength to Very Strong PS2-Very Strong
BP2 upgraded in strength to strong BP2-Strong
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
PM3 downgraded in strength to Supporting PM3-Supporting
For recessive disorders, detected in trans with a pathogenic variant PM3
PM3 upgraded in strength to Strong PM3-Strong
PM3 upgraded in strength to Very Strong PM3-Very Strong
BP6 upgraded in strength to strong BP6-Strong
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
PP5 upgraded in strength to Moderate PP5-Moderate
PP5 upgraded in strength to Strong PP5-Strong
PP5 upgraded in strength to Very Strong PP5-Very Strong
BP5 upgraded in strength to strong BP5-Strong
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
PP4 upgraded in strength to Moderate PP4-Moderate
PP4 upgraded in strength to Strong PP4-Strong
PP4 upgraded in strength to Very Strong PP4-Very Strong