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_000277.3(PAH):c.498C>G (p.Tyr166Ter)

Curation Version - 1.0
Curation History
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CA16020801

371373 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8fc3e56e-109a-44d4-885b-06bf023bf022

Approved on: 2022-01-22

Published on: 2022-06-28

HGVS expressions

NM_000277.3:c.498C>G

NM_000277.3(PAH):c.498C>G (p.Tyr166Ter)

NC_000012.12:g.102866607G>C

CM000674.2:g.102866607G>C

NC_000012.11:g.103260385G>C

CM000674.1:g.103260385G>C

NC_000012.10:g.101784515G>C

NG_008690.1:g.55996C>G

NG_008690.2:g.96804C>G

ENST00000553106.6:c.498C>G

ENST00000307000.7:c.483C>G

ENST00000549111.5:n.594C>G

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

ENST00000553106.5:c.498C>G

NM_000277.1:c.498C>G

NM_000277.2:c.498C>G

NM_001354304.1:c.498C>G

NM_001354304.2:c.498C>G

Pathogenic

PM3_Supporting PVS1 PP4_Moderate PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.498C>G (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay. It has been reported in multiple individuals, including in homozygosity in a classic PKU patient in the Uyger population. (PM3, PP4, PMID:31355225). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate.

PM3_Supporting

The patient in PMID: 31355225 is homozygous. 0.5pt

PVS1

Nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay.

PP4_Moderate

The patient in PMID: 31355225 is reported to have classic PKU with serum Phe levels >1200uM and BH4 deficiency ruled out by urinary pterin analysis, and determination of DHPR activity.

PM2

The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, and ESP.

Curation History

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