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.
ACMG variant classification (PAH)
Allele frequency above 0.015 (1.5%) BA1
Observed in the homozygous state in a healthy adult BS2
Allele frequency greater than expected for disease (>0.002, 0.2%) BS1
Absent/rare from controls in an ethnically-matched cohort population sample.
* Threshold: <0.0002 (0.02%).
PM2
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
Multiple lines of computational evidence suggest no impact on gene or gene product BP4
Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP3
PVS1 downgraded in strength to Moderate PVS1-Moderate
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PM5
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. PM4
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. PS1
PVS1 downgraded in strength to Strong PVS1-Strong
Null variant in a gene where loss of function is a known mechanism of disease. PVS1
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function
* Enzyme activity >85%
BS3-Supporting
PS3 downgraded in strength to Supporting PS3-Supporting
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 in vitro or in vivo functional studies supportive of a damaging effect
* PAH enzyme activity assay demonstrating enzyme activity <50%
* RT-PCR evidence of missplicing for non-canonical intronic variants
PS3
Lack of segregation in affected members of a family. BS4
Co-segregation with disease in multiple affected family members
* 1 affected family member + 3 unaffected segregations
PP1
Co-segregation with disease in multiple affected family members
* 2 affected segregations + 0 unaffected segregations
PP1-Moderate
Co-segregation with disease in multiple affected family members:
* 3 affected segregations + 0 unaffected segregations OR
* 2 affected segregations + 3 unaffected segregations
PP1-Strong
PS2 downgraded in strength to Moderate PS2-Moderate
De novo (paternity confirmed) in a patient with the disease and no family history. 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
Detected in trans with another variant:
* 2 compound heterozygotes (with VUS in trans)
* 2 homozygotes (allele drop out excluded)
PM3-Supporting
For recessive disorders, detected in trans with a pathogenic variant. PM3
For recessive disorders, detected in trans with a pathogenic variant.
* Compound heterozygous with 2 P/LP variants OR
* Compound heterozygous with 1 P/LP variant AND 2 homozygotes
PM3-Strong
For recessive disorders, detected in trans with a pathogenic variant.
* 4 compound heterozygotes with 3 P/LP variants OR
* 2 compound heterozygotes with 2 P/LP variants AND 4 homozygotes OR
* 3 compound heterozygotes with 2 P/LP variants AND 2 homozygotes
PM3-Very Strong
Variant found in a case with an alternate molecular basis for disease BP5
Phenotype specific for disease with single genetic etiology. PP4
Plasma Phe >120 µmol/L and exclusion of a defect of BH4 cofactor metabolism. PP4-Moderate