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_000277.3(PAH):c.1129del (p.Tyr377fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229356

634 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: efc3a0ee-cda3-4719-b5a2-d79415187014

Approved on: 2020-06-26

Published on: 2020-06-26

HGVS expressions

NM_000277.3:c.1129del

NM_000277.3(PAH):c.1129del (p.Tyr377fs)

NC_000012.12:g.102843717del

CM000674.2:g.102843717del

NC_000012.11:g.103237495del

CM000674.1:g.103237495del

NC_000012.10:g.101761625del

NG_008690.1:g.78887del

NG_008690.2:g.119695del

NM_000277.1:c.1129del

NM_000277.2:c.1129del

NM_001354304.1:c.1129del

NM_001354304.2:c.1129del

ENST00000307000.7:c.1114del

ENST00000549247.6:n.888del

ENST00000551114.2:n.791del

ENST00000553106.5:c.1129del

ENST00000635477.1:n.233del

ENST00000635528.1:n.644del

Pathogenic

PP4 PM2 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1129delT (p.Tyr377Thrfs) variant in PAH has been reported in an Icelandic PKU cohort. (PP4; PMID: 9450182). This variant is absent from gnomAD (PM2). It is a frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.

PP4

Detected in PKU Icelandic cohort.

We have investigated the molecular basis of phenylketonuria (PKU) in 17 Icelandic patients and found 9 different mutations in the phenylalanine hydroxylase gene. One novel mutation, Y377fsdelT, accounts for more than 40% of the mutant chromosomes. PubMed:9450182

PM2

Absent from gnomAD with good coverage (>252,000 alleles)

PVS1

Frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function

Curation History

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