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.1147C>T (p.Gln383Ter)

CA16020949

370701 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 68a79c42-9ba2-46da-86d0-0f38d4775853

HGVS expressions

NM_000277.2:c.1147C>T

NM_000277.2(PAH):c.1147C>T (p.Gln383Ter)

NC_000012.12:g.102843698G>A

CM000674.2:g.102843698G>A

NC_000012.11:g.103237476G>A

CM000674.1:g.103237476G>A

NC_000012.10:g.101761606G>A

NG_008690.1:g.78905C>T

NG_008690.2:g.119713C>T

NM_000277.1:c.1147C>T

NM_001354304.1:c.1147C>T

NM_000277.3:c.1147C>T

ENST00000307000.7:c.1132C>T

ENST00000549247.6:n.906C>T

ENST00000551114.2:n.809C>T

ENST00000553106.5:c.1147C>T

ENST00000635477.1:n.251C>T

ENST00000635528.1:n.662C>T

Pathogenic

PVS1 PP4 PM3 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1147C>T (p.Gln383Ter) variant in PAH is a nonsense variant predicted to undergo NMD, present in all biologically relevant transcripts, absent from all populations databases. It has been identified in a patient with classic PKU as homozygous, and in trans with a pathogenic variant (R408W), although defect in BH4 metabolism was not excluded in either patient. (PMID: 24350308, 22763404). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PVS1

Nonsense variant. Predicted to undergo NMD, present in all biologically relevant transcripts.

PP4

two independent patients in two publications with classic PKU, BH4 not excluded in either pub PMID: 24350308, PMID: 22763404

classic PKU PubMed:22763404

classic PKU PubMed:24350308

PM3

homozygous (Ham 2012), R408W (Bik-Multanowski), both patients with classic PKU

homozygote with classic PKU PubMed:22763404

in trans with R408W in a patient with classic PKU PubMed:24350308

PM2

Absent from both ExAC and gnomAD

Approved on: 2018-12-09

Published on: 2019-04-06

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