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.824C>G (p.Pro275Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229791

102854 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f7fde206-5b4d-4940-8eec-742dbe7ee761

Approved on: 2018-12-09

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.824C>G

NM_000277.2(PAH):c.824C>G (p.Pro275Arg)

NC_000012.12:g.102852833G>C

CM000674.2:g.102852833G>C

NC_000012.11:g.103246611G>C

CM000674.1:g.103246611G>C

NC_000012.10:g.101770741G>C

NG_008690.1:g.69770C>G

NG_008690.2:g.110578C>G

NM_000277.1:c.824C>G

NM_001354304.1:c.824C>G

NM_000277.3:c.824C>G

ENST00000307000.7:c.809C>G

ENST00000549247.6:n.583C>G

ENST00000553106.5:c.824C>G

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3 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.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3.

PP4_Moderate

BH4 defect excluded in all patients (Bueno 2013) PMID: 23514811

BH4 defect excluded in all patients. Single patient, genotype known with moderate PKU PubMed:23514811

PP3

In silico agree damaging. REVEL = 0.964

PM2

Absent from population databases

PM3

I68T (pathogenic in clinvar) (Bueno, 2013)

Single patient, in trans I65T with moderate PKU (600-1200umol/L) PubMed:23514811

PM5

p.Pro275Ser and p.Pro275Leu are both LP in ClinVar

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.