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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.3(PAH):c.461A>T (p.Tyr154Phe)

CA16020795

619705 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 536508bf-5b5e-4806-a2a2-3490aeaa8622

HGVS expressions

NM_000277.3:c.461A>T

NM_000277.3(PAH):c.461A>T (p.Tyr154Phe)

NC_000012.12:g.102866644T>A

CM000674.2:g.102866644T>A

NC_000012.11:g.103260422T>A

CM000674.1:g.103260422T>A

NC_000012.10:g.101784552T>A

NG_008690.1:g.55959A>T

NG_008690.2:g.96767A>T

NM_000277.1:c.461A>T

NM_000277.2:c.461A>T

NM_001354304.1:c.461A>T

ENST00000307000.7:c.446A>T

ENST00000549111.5:n.557A>T

ENST00000551988.5:n.530+10818A>T

ENST00000553106.5:c.461A>T

Likely Pathogenic

PM3_Supporting PP4_Moderate PP3 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.461A>T (p.Tyr154Phe) variant in PAH has been reported in 3 individuals with PKU (BH4 deficiency excluded). (PMID: 24368688, 31332730). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant c.1315+1G>A (IVS12+1G>A) (PMID: 24368688). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.

PM3_Supporting

Detected with c.1315+1G>A (IVS12+1G>A) (pathogenic 13 submitters) and p.G103C (VUS) PMID: 24368688

PP4_Moderate

reported in 3 PKU patients PMID: 24368688, 31332730. BH4 deficiency excluded biochemically and sequencing of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes.

PubMed:31332730

PubMed:24368688

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.959

PM2

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

Approved on: 2020-01-26

Published on: 2020-01-26

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