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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.

ACMG variant classification (PAH)

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

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

Computational And Predictive Data

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

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

Null variant in a gene where loss of function is a known mechanism of disease. PVS1

Functional Data

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function
* Enzyme activity >85% BS3-Supporting

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

Segregation Data

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

De novo Data

De novo (paternity confirmed) in a patient with the disease and no family history. PS2

Allelic Data

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

Other Data

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

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