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_000277.2(PAH):c.865G>C (p.Gly289Arg)

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Curation History
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CA229830

102882 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f6f2fb05-fc57-4712-ad91-80732194a1e8

Approved on: 2018-12-09

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.865G>C

NM_000277.2(PAH):c.865G>C (p.Gly289Arg)

NC_000012.12:g.102851734C>G

CM000674.2:g.102851734C>G

NC_000012.11:g.103245512C>G

CM000674.1:g.103245512C>G

NC_000012.10:g.101769642C>G

NG_008690.1:g.70869G>C

NG_008690.2:g.111677G>C

NM_000277.1:c.865G>C

NM_001354304.1:c.865G>C

NM_000277.3:c.865G>C

ENST00000307000.7:c.850G>C

ENST00000549247.6:n.624G>C

ENST00000551114.2:n.527G>C

ENST00000553106.5:c.865G>C

ENST00000635477.1:n.26G>C

Pathogenic

PP4_Moderate PS1 PM3 PM2 PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.865G>C (p.Gly289Arg) variant in PAH is absent from population databases and predicted deleterious with in silico prediction software. This is the same amnio acid change as a previously established pathogenic variant (c.865G>A; p.Gly289Arg). It has been identified in trans with a pathogenic variant (R155C, curated by the PAH EP), and a defect in BH4 metabolism was excluded (PMID: 22921945). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS1, PM2, PM3, PP3.

PP4_Moderate

BH4 defect excluded. Single patient with mild PKU. PMID: 22921945

BH4 defect excluded in all patients. Single patient with mild PKU PubMed:22921945

PS1

NM_000277.2(PAH):c.865G>A (p.Gly289Arg)

PM3

In trans with R155C, which has been independently curated by the Inborn Errors workgroup as LP (Bueno 2013)

Single patient with mild PKU in trans wtih R155C, which has been curated by the Metabolism WG as Likely Pathogenic PubMed:23514811

PM2

Absent from all population databases

PP3

In silico all predict damaging effect. REVEL=0.98

Curation History

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