Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000277.2(PAH):c.498C>A (p.Tyr166Ter)

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CA229583

102702 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 76342745-0175-4795-ab71-e314ef54d447

Approved on: 2019-04-08

Published on: 2019-04-08

HGVS expressions

NM_000277.2:c.498C>A

NM_000277.2(PAH):c.498C>A (p.Tyr166Ter)

NC_000012.12:g.102866607G>T

CM000674.2:g.102866607G>T

NC_000012.11:g.103260385G>T

CM000674.1:g.103260385G>T

NC_000012.10:g.101784515G>T

NG_008690.1:g.55996C>A

NG_008690.2:g.96804C>A

NM_000277.1:c.498C>A

NM_001354304.1:c.498C>A

NM_000277.3:c.498C>A

ENST00000307000.7:c.483C>A

ENST00000549111.5:n.594C>A

ENST00000551988.5:n.530+10855C>A

ENST00000553106.5:c.498C>A

Pathogenic

PVS1 PP4 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.498C>A (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in individuals with Classic PKU in German and Chinese cohorts. (PP4, PMID:16256386; 10394930). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). This variant was detected with multiple known pathogenic variants (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PVS1

Nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function

PP4

Y166X reported on 6 alleles in patients with classical PKU. PMID: 16256386

Y166X reported on 6 alleles in patients with classical PKU. PAH deficiency was diagnosed by conventional biochemical methods. Classic PKU (Phe > 1200 umol/L). PubMed:16256386

PM3

Detected with 5 known pathogenic variants: R111X (P, 7 submitters), IVS4+1G>A (P/LP, 4 submitters), Y204C (P/LP, 4 submitters), Y356X (c.1068C>A P, 5 submitters), V399V (P, 5 submitters)

Genotypes: R111X (P, 7 submitters)+ Y166X, Y166X + IVS4+1G>A (P/LP, 4 submitters), Y166X + Y204C (P/LP, 4 submitters), Y166X + Y356X (c.1068C>A P, 5 submitters), Y166X + V399V (P, 5 submitters) PubMed:16256386

PM2

Absent from controls ExAC, 1000 Genomes, or ESP

Curation History

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