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_000277.2(PAH):c.1172G>C (p.Ser391Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA357240

225136 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1090b77b-cd07-48e8-8b33-b7e9ceb00977

Approved on: 2020-03-07

Published on: 2020-03-07

HGVS expressions

NM_000277.2:c.1172G>C

NM_000277.2(PAH):c.1172G>C (p.Ser391Thr)

NC_000012.12:g.102843673C>G

CM000674.2:g.102843673C>G

NC_000012.11:g.103237451C>G

CM000674.1:g.103237451C>G

NC_000012.10:g.101761581C>G

NG_008690.1:g.78930G>C

NG_008690.2:g.119738G>C

NM_000277.1:c.1172G>C

NM_001354304.1:c.1172G>C

NM_000277.3:c.1172G>C

NM_001354304.2:c.1172G>C

ENST00000307000.7:c.1157G>C

ENST00000549247.6:n.931G>C

ENST00000551114.2:n.834G>C

ENST00000553106.5:c.1172G>C

ENST00000635477.1:n.276G>C

ENST00000635528.1:n.687G>C

Likely Pathogenic

PP4_Moderate PM3 PM2

PP3 PM5

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1172G>C (p.Ser391Thr) variant in PAH has been reported in at least one individual with MHP (BH4 deficiency excluded, PMID: 30747360, 29499199) in trans with pathogenic variant p.Val399= (PMID: 29316886). This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

PP4_Moderate

Seen in an individual with MHP, All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay PMID: 30747360, 29499199

PubMed:30747360

PubMed:29316886

PubMed:29499199

Seen in an individual with MHP, BH4 cofactor activity was not excluded. PubMed:25894915

PM3

Detected in trans with V399V (pathogenic 5 submitters) PMID: 29316886

Seen in trans in an individual with MHP in trans with V399V (pathogenic in database) PubMed:25894915

PM2

Absent from control databases.

PP3

Conflicting effects reported- Polyphen2: Probably Damaging. SIFT: Deleterious AND tolerated. MutationTaster: Deleterious

PM5

Ser391Gly likely pathogenic

Curation History

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