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

CA16020943

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bfe666a9-8374-404a-9e7a-30ffe15d7f01

HGVS expressions

NM_000277.3:c.1118C>A

NC_000012.12:g.102843727G>T

CM000674.2:g.102843727G>T

NC_000012.11:g.103237505G>T

CM000674.1:g.103237505G>T

NC_000012.10:g.101761635G>T

NG_008690.1:g.78876C>A

NG_008690.2:g.119684C>A

NM_000277.1:c.1118C>A

NM_000277.2:c.1118C>A

NM_001354304.1:c.1118C>A

NM_001354304.2:c.1118C>A

ENST00000307000.7:c.1103C>A

ENST00000549247.6:n.877C>A

ENST00000551114.2:n.780C>A

ENST00000553106.5:c.1118C>A

ENST00000635477.1:n.222C>A

ENST00000635528.1:n.633C>A

Likely Pathogenic

PM3_Supporting PP3 PM2 PP4_Moderate

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1118C>A (p.Ala373Asp) variant in PAH is absent from population databases (PM2). A deleterious effect is predicted in SIFT, PolyPhen-2, MutationTaster, and REVEL = 0.958 (PP3). The variant was detected with R158Q, pathogenic in ClinVar, phase unknown (PM3_Supporting). Variant was detected in patient with HPA defined as excessive blood levels (>120 μmol/l) of phenylalanine (BH4 deficiency ruled out; PP4_Moderate; PMID: 23942198). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3, PM3_Supporting.

PM3_Supporting

PMID:23942198 - A373D detected with R158Q, pathogenic in ClinVar, phase unknown - 0.5 points

PubMed:23942198

PP3

Predicted damaging by SIFT, probably damaging by PolyPhen, and disease causing by Mutation Taster. REVEL = 0.958.

PM2

absent from population databases

PP4_Moderate

C10 is part of a cohort of 95 HPA patients with HPA defined as excessive blood levels (>120 μmol/l) of phenylalanine. A defect in BH4 cofactor metabolism was excluded by sequencing GCH1, PTS, and QDPR.

PM5

Same residue as c.1117G>A (p.Ala373Thr) with no classification provided in ClinVar, but curated by PAH VCEP as likely pathogenic (in progress).

Approved on: 2020-03-26

Published on: 2020-03-26

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