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

Variant: NM_000277.3(PAH):c.1237C>A (p.Arg413Ser)

CA229411

102575 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8f012027-88de-4c03-965a-c6f579340b1d

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.1237C>A

NM_000277.3(PAH):c.1237C>A (p.Arg413Ser)

NC_000012.12:g.102840478G>T

CM000674.2:g.102840478G>T

NC_000012.11:g.103234256G>T

CM000674.1:g.103234256G>T

NC_000012.10:g.101758386G>T

NG_008690.1:g.82125C>A

NG_008690.2:g.122933C>A

ENST00000553106.6:c.1237C>A

ENST00000307000.7:c.1222C>A

ENST00000551114.2:n.899C>A

ENST00000553106.5:c.1237C>A

ENST00000635477.1:c.341C>A

ENST00000635528.1:n.752C>A

NM_000277.1:c.1237C>A

NM_000277.2:c.1237C>A

NM_001354304.1:c.1237C>A

NM_001354304.2:c.1237C>A

Pathogenic

PM2_Supporting PP4_Moderate PM5 PP3_Strong PS3_Supporting

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1237C>A (p.Arg413Ser) variant in PAH has been reported in 1 patient with mild hyperphenylalenemia (BH4 deficiency excluded). This variant has been reported in at least 2 in vitro studies showing <50% PAH activity as compared to wild type. This variant is absent from population databases, and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, REVEL = 0.934. This variant is at the same codon as c.1238G>C (p.Arg413Pro) which has been curated as pathogenic by the ClinGen PAH VCEP (ClinVarID:592). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP4_Moderate, PP3_strong.

PM2_Supporting

Variant absent from gnomAD v2.1.1

PP4_Moderate

PMID: 9634518 - R413S detected in 1 patient with mild hyperphenylalenemia (Phe < 600 mmol/liter), BH4 deficiency excluded

PM5

c.1238G>C (p.Arg413Pro) has been curated as pathogenic by the ClinGen PAH VCEP (ClinVarID:592); c.1237C>G (p.Arg413Gly) - not reported in ClinVar; not yet curated by ClinGen PAH VCEP; c.1237C>T (p.Arg413Cys) curated by ClinGen PAH VCEP as VUS (VarID:102576)

PP3_Strong

Predicted deleterious by SIFT, PolyPhen2, MutationTaster, REVEL = 0.934.

PS3_Supporting

2 in vitro studies showing 32-34% PAH activity . PMID: 30037505, PMID: 10479481

20-40% enzyme activity, 12 variants tested, none benign PubMed:10479481

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.