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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

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

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

PS4 downgraded in strength to Supporting PS4-Supporting

PM2 downgraded in strength to Supporting PM2-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

PS4 upgraded in strength to Very Strong PS4-Very Strong

PM2 upgraded in strength to Very Strong PM2-Very Strong

Computational And Predictive Data

BP3 upgraded in strength to strong BP3-Strong

BP7 upgraded in strength to strong BP7-Strong

BP4 upgraded in strength to strong BP4-Strong

BP1 upgraded in strength to strong BP1-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

PS1 downgraded in strength to Supporting PS1-Supporting

PM4 downgraded in strength to Supporting PM4-Supporting

PVS1 downgraded in strength to Supporting PVS1-Supporting

PM5 downgraded in strength to Supporting PM5-Supporting

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

PP3 upgraded in strength to Moderate PP3-Moderate

PS1 downgraded in strength to Moderate PS1-Moderate

PVS1 downgraded in strength to Moderate 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

PP3 upgraded in strength to Strong PP3-Strong

PM5 upgraded in strength to Strong PM5-Strong

PM4 upgraded in strength to Strong PM4-Strong

Same amino acid change as an established pathogenic variant PS1

PVS1 downgraded in strength to Strong PVS1-Strong

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

PM5 upgraded in strength to Very Strong PM5-Very Strong

PS1 upgraded in strength to Very Strong PS1-Very Strong

PP3 upgraded in strength to Very Strong PP3-Very Strong

PM4 upgraded in strength to Very Strong PM4-Very Strong

Functional Data

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

PS3 downgraded in strength to Supporting PS3-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

PP2 upgraded in strength to Moderate PP2-Moderate

PS3 downgraded in strength to Moderate PS3-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

PM1 upgraded in strength to Strong PM1-Strong

PP2 upgraded in strength to Strong PP2-Strong

Well-established functional studies show a deleterious effect PS3

PS3 upgraded in strength to Very Strong PS3-Very Strong

PM1 upgraded in strength to Very Strong PM1-Very Strong

PP2 upgraded in strength to Very Strong PP2-Very Strong

Segregation Data

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

De novo Data

PM6 downgraded in strength to Supporting PM6-Supporting

PS2 downgraded in strength to Supporting PS2-Supporting

PS2 downgraded in strength to Moderate PS2-Moderate

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

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

Allelic Data

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

Other Database

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

Other Data

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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
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