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.535T>C (p.Tyr179His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229615

102730 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 322ac92c-85df-4b41-b751-f5b2b91fb875

Approved on: 2022-12-09

Published on: 2022-12-09

HGVS expressions

NM_000277.3:c.535T>C

NM_000277.3(PAH):c.535T>C (p.Tyr179His)

NC_000012.12:g.102855307A>G

CM000674.2:g.102855307A>G

NC_000012.11:g.103249085A>G

CM000674.1:g.103249085A>G

NC_000012.10:g.101773215A>G

NG_008690.1:g.67296T>C

NG_008690.2:g.108104T>C

ENST00000553106.6:c.535T>C

ENST00000307000.7:c.520T>C

ENST00000549111.5:n.631T>C

ENST00000551988.5:n.556T>C

ENST00000553106.5:c.535T>C

NM_000277.1:c.535T>C

NM_000277.2:c.535T>C

NM_001354304.1:c.535T>C

NM_001354304.2:c.535T>C

Likely Pathogenic

PM3_Strong PP4_Moderate PP3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.535T>C (p.Tyr179His) variant in PAH has been reported in multiple individuals with PKU, including in patients with classic PKU in whom BH4 deficiency has been excluded (PMID: 29997390, PMID: 16256386, PMID: 20920871, PMID: 32668217, PMID: 30389586). p.Tyr179His has been detected with multiple variants classified as likely pathogenic or pathogenic by PAH VCEP, including p.Arg176*, c.1066-11G>A, c.1199+1G>C, p.Ala403Val, p.Ile406Met, p.Arg408Trp, p.Val230Ile (PMID: 32668217). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3.

PM3_Strong

PM3_Strong applies based on Hillert cases. Some of the previous papers may represent the same patients described in the Hillert paper. There are 7 compound heterozygous cases (with phase unconfirmed, so 3.5 pts)

PP4_Moderate

Observed on at least 12 alleles, classic PKU for at least 6 cases when type described. At least 2 cases of compound heterozygotes with serum PAH >1200 μmol/L and BH4 deficiency excluded.

PP3

Damaging in SIFT, PP-2, MutationTaster, REVEL=0.964

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

PM5

Y179N is LP in ClinVar

Curation History

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