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.506G>C (p.Arg169Pro)

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Curation History
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CA386299458

446524 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 17a486f7-ffbd-4259-8b78-60b54b661011

Approved on: 2021-03-26

Published on: 2021-03-26

HGVS expressions

NM_000277.2:c.506G>C

NM_000277.2(PAH):c.506G>C (p.Arg169Pro)

NC_000012.12:g.102866599C>G

CM000674.2:g.102866599C>G

NC_000012.11:g.103260377C>G

CM000674.1:g.103260377C>G

NC_000012.10:g.101784507C>G

NG_008690.1:g.56004G>C

NG_008690.2:g.96812G>C

ENST00000307000.7:c.491G>C

ENST00000553106.5:c.506G>C

NM_000277.1:c.506G>C

NM_001354304.1:c.506G>C

NM_000277.3:c.506G>C

NM_001354304.2:c.506G>C

Uncertain Significance

PP3 PM5 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.506G>C (p.Arg169Pro) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 446524); no further information is provided. At the time of review, the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant is predicted damaging by multiple lines of computational evidence (PP3). It is absent in gnomAD (PM2). Other missense variants at this site are pathogenic/likely pathogenic – p.Arg169Ser (variant ID 932262), p.Arg169His (variant ID 102706), p.Arg169Gly (variant ID 551103), and p.Arg169Cys (variant ID 125436) (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.

PP3

The variant results in the substitution of a moderately conserved Arginine residue with Proline; the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., predicted deleterious in SIFT, Polyphen2, Mutation Taster; REVEL = 0.861) (PP3).

PM5

p.Arg169Ser is pathogenic by PAH VCEP; p.Arg169His and p.Arg169Cys are Likely Pathogenic per PAH VCEP; p.Arg169Gly is US by one clinical laboratory.

PM2

Absent in gnomAD

Curation History

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