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_000277.3(PAH):c.1132A>T (p.Thr378Ser)

CA229358

102535 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5c6b7e78-f252-447a-9431-c72f959ed420

HGVS expressions

NM_000277.3:c.1132A>T

NM_000277.3(PAH):c.1132A>T (p.Thr378Ser)

NC_000012.12:g.102843713T>A

CM000674.2:g.102843713T>A

NC_000012.11:g.103237491T>A

CM000674.1:g.103237491T>A

NC_000012.10:g.101761621T>A

NG_008690.1:g.78890A>T

NG_008690.2:g.119698A>T

NM_000277.1:c.1132A>T

NM_000277.2:c.1132A>T

NM_001354304.1:c.1132A>T

NM_001354304.2:c.1132A>T

ENST00000307000.7:c.1117A>T

ENST00000549247.6:n.891A>T

ENST00000551114.2:n.794A>T

ENST00000553106.5:c.1132A>T

ENST00000635477.1:n.236A>T

ENST00000635528.1:n.647A>T

Uncertain Significance

BP4 PM3_Supporting PM2 PP4_Moderate

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3:c.1132A>T (p.Thr378Ser) missense variant has been reported in one mild PKU patient (PMID: 10767174), with compound heterozygous genotype of Thr378Ser with Arg243Gln (ClinVar591; Pathogenic). This variant is absent from 1000G, ESP, and gnomAD databases. It is predicted not to a have damaging effect: SIFT: Tolerated, PolyPhen: Benign, MutationTaster: Polymorphism. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied:PM2, PM3_supporting, PP4_moderate, BP4.

BP4

Multiple lines of computational evidence suggest no impact on gene or gene product; SIFT predicts Tolerated, PolyPhen predicts Benign, and MutationTaster predicts Polymorphism. Additionally no impact on splice sites is predicted by either Human Splicing Finder or MaxEntScan.

PM3_Supporting

Mild PKU Patient F15 of PMID: 10767174 is compound heterozygous for Thr378Ser and Arg243Gln (ClinVar 591; Pathogenic). Confirmation of phase was not reported. 0.5pt

PM2

This variant is absent from population databases including gnomAD.

PP4_Moderate

Patient F15 of PMID: 10767174 was characterized as having mild PKU with a Phe level of 1211uM. Evaluated urinary pterin levels and dihydropteridinereductase activity to exclude defects of BH4 cofactor metabolism.

Approved on: 2020-05-14

Published on: 2020-05-14

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