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.1030G>C (p.Gly344Arg)

CA229287

102480 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 188919c9-703a-413b-bc52-514b81efd9ea

HGVS expressions

NM_000277.2:c.1030G>C

NM_000277.2(PAH):c.1030G>C (p.Gly344Arg)

ENST00000553106.6:c.1030G>C

ENST00000307000.7:c.1015G>C

ENST00000549247.6:n.789G>C

ENST00000551114.2:n.692G>C

ENST00000553106.5:c.1030G>C

ENST00000635477.1:n.134G>C

ENST00000635528.1:n.545G>C

NM_000277.1:c.1030G>C

NM_001354304.1:c.1030G>C

NM_000277.3:c.1030G>C

NM_001354304.2:c.1030G>C

NC_000012.12:g.102844371C>G

CM000674.2:g.102844371C>G

NC_000012.11:g.103238149C>G

CM000674.1:g.103238149C>G

NC_000012.10:g.101762279C>G

NG_008690.1:g.78232G>C

NG_008690.2:g.119040G>C

Uncertain Significance

PM3_Supporting PP3 PP4 PM2

PS3 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1030G>C (p.Gly344Arg) variant in PAH has been reported in 1 individual with with classic PKU, detected with pathogenic variant c.1315+1G>A (aka IVS12+1G>A, PMID: 23430918). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Val, p.Gly344Asp and p.Gly344Ser are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2, PM3_supporting.

PM3_Supporting

Detected with IVS12+1G>A, pathogenic in Clinvar, Var ID: 576. Parental analysis not reported. PMID: 10679941

PP3

Predicted deleterious by PolyPhen, MutationTaster, and SIFT.

PP4

Seen in one individual with classic PKU, Cofactor deficiency was excluded by the BH4 test. PMID: 23430918

PM2

Absent from controls in ExAC, 1000 Genomes, ESP.

PS3

Mutation predicted to affect protein stability. Severe effect predicted. No in vitro study.

PM5

G334V likely pathogenic by PAH VCEP, VUS in Clinvar. G344D and S likely pathogenic by PAH VCEP.

Approved on: 2021-06-11

Published on: 2021-06-11

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