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]

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Variant: NM_000277.2(PAH):c.827T>G (p.Met276Arg)

CA229797

102858 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 81e99b34-e26c-4f1b-af94-b863ba7c1e11

HGVS expressions

NM_000277.2:c.827T>G

NM_000277.2(PAH):c.827T>G (p.Met276Arg)

NC_000012.12:g.102852830A>C

CM000674.2:g.102852830A>C

NC_000012.11:g.103246608A>C

CM000674.1:g.103246608A>C

NC_000012.10:g.101770738A>C

NG_008690.1:g.69773T>G

NG_008690.2:g.110581T>G

NM_000277.1:c.827T>G

NM_001354304.1:c.827T>G

NM_000277.3:c.827T>G

ENST00000307000.7:c.812T>G

ENST00000549247.6:n.586T>G

ENST00000553106.5:c.827T>G

Likely Pathogenic

PP3 PP4 PM2 PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.827T>G (p.Met276Arg) variant in PAH is absent from population databases and predicted damaging by in silico models. It is a novel missense change at an amino acid residue where different pathogenic missense changes have been reported (p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP). It has been reported in individuals with phenylkeonuria in the literature, although a defect in the metabolism of BH4 has not been excluded as a cause for elevated phenylalanine in any of these patients (PMID: 23932990, 15300621). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3.

PP3

In silico agree on damaging effet. REVEL=0.882

PP4

Listed in Zhang 2004 (PMID: 15300621) in a PKU cohort, no other information provided, and Zu 2013 (PMID: 23932990) as an allele with unclassified BH4 responsiveness.

Listed in paper with no supporting information provided PubMed:15300621

Listed as an allele identified in their PKU cohort with undefined BH4 responsiveness. No additional patient information or Phe levels provided. PubMed:23932990

PM2

Absent from population databases

PM5

p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP

Approved on: 2018-12-10

Published on: 2019-04-05

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