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]

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

CA16020801

371373 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2 PP4_Moderate PVS1 PM3_Supporting

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.

PM2

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

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.

PVS1

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

PM3_Supporting

The patient in PMID: 31355225 is homozygous. 0.5pt

Approved on: 2022-01-22

Published on: 2022-06-28

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