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_000277.2(PAH):c.1031G>T (p.Gly344Val)

CA229290

102482 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f7e94577-2091-4306-a052-fb3f613b3660

HGVS expressions

NM_000277.2:c.1031G>T

NM_000277.2(PAH):c.1031G>T (p.Gly344Val)

ENST00000553106.6:c.1031G>T

ENST00000307000.7:c.1016G>T

ENST00000549247.6:n.790G>T

ENST00000551114.2:n.693G>T

ENST00000553106.5:c.1031G>T

ENST00000635477.1:n.135G>T

ENST00000635528.1:n.546G>T

NM_000277.1:c.1031G>T

NM_001354304.1:c.1031G>T

NM_000277.3:c.1031G>T

NM_001354304.2:c.1031G>T

NC_000012.12:g.102844370C>A

CM000674.2:g.102844370C>A

NC_000012.11:g.103238148C>A

CM000674.1:g.103238148C>A

NC_000012.10:g.101762278C>A

NG_008690.1:g.78233G>T

NG_008690.2:g.119041G>T

Uncertain Significance

PP4 PP3 PM3_Supporting PM2

PP1 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.1031G>T (p.Gly344Val) variant in PAH has been reported in 2 siblings with classic PKU, detected with pathogenic variant p.R243Q. (PMID: 10679941). 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.Gly344Asp, p.Gly344Ser and p.Gly344Arg 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: PM2, PM3_supporting, PP3, PP4.

PP4

Seen in two siblings with Classic PKU with R243Q. Cofactor deficiency was excluded by the BH4 test PMID: 10679941

Seen in two siblings with Classic PKU, in trans with R243Q. PubMed:10679941

PP3

Predicted deleterious by SIFT, PolyPhen, and MutationTaster.

PM3_Supporting

Detected with R243Q in 2 siblings, pathogenic in Clinvar (Var ID 591).

PM2

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

PP1

Cosegregation with disease in 2 affected siblings, but parental status or other siblings not reported. PMID: 10679941

PM5

G344D likely pathogenic by PAH VCEP; G344R and G344S likely pathogenic by PAH VCEP

Approved on: 2021-06-11

Published on: 2021-06-11

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