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_000277.1(PAH):c.1054G>C (p.Gly352Arg)

CA229307

102496 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1bf842f3-8dc0-4cb4-b3d7-bbfe345c2340

HGVS expressions

NM_000277.1:c.1054G>C

NM_000277.1(PAH):c.1054G>C (p.Gly352Arg)

ENST00000553106.6:c.1054G>C

ENST00000307000.7:c.1039G>C

ENST00000549247.6:n.813G>C

ENST00000551114.2:n.716G>C

ENST00000553106.5:c.1054G>C

ENST00000635477.1:n.158G>C

ENST00000635528.1:n.569G>C

NM_000277.2:c.1054G>C

NM_001354304.1:c.1054G>C

NM_000277.3:c.1054G>C

NM_001354304.2:c.1054G>C

NC_000012.12:g.102844347C>G

CM000674.2:g.102844347C>G

NC_000012.11:g.103238125C>G

CM000674.1:g.103238125C>G

NC_000012.10:g.101762255C>G

NG_008690.1:g.78256G>C

NG_008690.2:g.119064G>C

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2

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.1054G>C (p.Gly352Arg) variant in PAH has been reported in multiple individuals with classical and mild PKU (BH4 deficiency excluded) (PMID 9634518, 29316886, 30747360). This variant is absent in population databases. This variant was detected in trans with pathogenic variant p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. Another missense variant at the same amino acid, p.Gly352Cys, has no assertion in ClinVar. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP4_Moderate

PMID 9634518: identified in two patients, classified as Classic PKU variant. PMID: 29316886 reported in 1 patient with mPKU (Phe 980 umol/L). PMID: 30747360: All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples.

PMID 9634518: identified in two patients, classified as Classic PKU variant. Excluded other causes (BH4 deficiency). PubMed:9634518

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster, REVEL=0.984.

PM3

Detected with p.Arg243Gln (P- 10 submitters), variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 29316886

PM2

Absent from controls in ExAC, 1000 Genomes, and ESP

PM5

p.Gly352Cys no assertion in ClinVar

Approved on: 2021-02-14

Published on: 2021-06-09

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