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.1127del (p.Asn376fs)

Curation Version - 1.0
Curation History
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CA229355

102532 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d883bb43-2a44-4d28-89a5-37dc377951fc

Approved on: 2023-10-15

Published on: 2023-10-15

HGVS expressions

NM_000277.3:c.1127del

NM_000277.3(PAH):c.1127del (p.Asn376fs)

NC_000012.12:g.102843721del

CM000674.2:g.102843721del

NC_000012.11:g.103237499del

CM000674.1:g.103237499del

NC_000012.10:g.101761629del

NG_008690.1:g.78885del

NG_008690.2:g.119693del

ENST00000553106.6:c.1127del

ENST00000307000.7:c.1112del

ENST00000549247.6:n.886del

ENST00000551114.2:n.789del

ENST00000553106.5:c.1127del

ENST00000635477.1:c.231del

ENST00000635528.1:n.642del

NM_000277.1:c.1127del

NM_000277.2:c.1127del

NM_001354304.1:c.1127del

NM_001354304.2:c.1127del

Pathogenic

PVS1 PP4 PM2_Supporting PM3_Supporting

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1127del (p.Asn376fs) variant in PAH is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a Mexican patient with classic PKU with the pathogenic variant c.1066-11G>A (PMID: 24941924; PP4, PM3_supporting). This variant has an extremely low frequency in gnomAD (MAF=0.00002895). In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PM3_supporting, PP4.

PVS1

Frameshift variant at amino acid 376 in exon 11 with termination codon predicted at amino acid 400 (exon 11/13). NMD predicted.

PP4

Reported in a Mexican patient with classic PKU. BH4 deficiency not reportedly assessed. PMID: 24941924

PM2_Supporting

extremely low frequency in gnomAD (MAF=0.00002895)

PM3_Supporting

Detected with pathogenic variant c.1066-11G>A, phasing not confirmed.

Curation History

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