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_000277.3(PAH):c.1001G>C (p.Cys334Ser)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA229263

102464 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bffa79b5-d67a-4083-b12e-2d5e84071018

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.1001G>C

NM_000277.3(PAH):c.1001G>C (p.Cys334Ser)

NC_000012.12:g.102844400C>G

CM000674.2:g.102844400C>G

NC_000012.11:g.103238178C>G

CM000674.1:g.103238178C>G

NC_000012.10:g.101762308C>G

NG_008690.1:g.78203G>C

NG_008690.2:g.119011G>C

ENST00000553106.6:c.1001G>C

ENST00000307000.7:c.986G>C

ENST00000549247.6:n.760G>C

ENST00000551114.2:n.663G>C

ENST00000553106.5:c.1001G>C

ENST00000635477.1:c.105G>C

ENST00000635528.1:n.516G>C

NM_000277.1:c.1001G>C

NM_000277.2:c.1001G>C

NM_001354304.1:c.1001G>C

NM_001354304.2:c.1001G>C

Likely Pathogenic

PP3_Strong PM2_Supporting PM3_Supporting PP4

PM5

Evidence Links 0

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.1001G>C (p.Cys334Ser) variant in PAH has been reported in 2 patients with mild PKU/HPA. (BH4 deficiency not ruled out. PMID: 8632937, 10693064). It was detected with pathogenic variant p.F299C (unknown phase). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.976. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PP4, PM3_supporting.

PP3_Strong

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.976.

PM2_Supporting

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3_Supporting

Detected with F299C (P, 5 submitters), parental analysis not reported

PP4

Detected in multiple patients with mild PKU/HPA. BH4 deficiency not ruled out. PMID: 8632937, 10693064

PM5

The current variant is the only missense variant found in this codon in ClinVar.

Curation History

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