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

CA16021000

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dd4c9b27-d04f-4738-bae3-de4d0ef5faad

HGVS expressions

NM_001354304.2:c.667_674dup

NM_000277.1:c.667_674dup

NM_000277.2:c.667_674dup

NM_001354304.1:c.667_674dup

NM_000277.3:c.667_674dup

ENST00000307000.7:c.652_659dup

ENST00000549111.5:n.763_770dup

ENST00000553106.5:c.667_674dup

NC_000012.12:g.102855168_102855175dup

CM000674.2:g.102855168_102855175dup

NC_000012.11:g.103248946_103248953dup

CM000674.1:g.103248946_103248953dup

NC_000012.10:g.101773076_101773083dup

NG_008690.1:g.67428_67435dup

NG_008690.2:g.108236_108243dup

Pathogenic

PP4 PVS1 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This variant c.667_674dup (p.Gln226ThrfsTer?) in PAH was documented in a patient with PAH deficiency (>120 μmol/L Phe) in the Czech Republic (PMID: 23357515). This is a frameshift variant in exon 6 out of 13 coding exons, predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4

PP4

This variant was documented 1 time in a patient with PAH deficiency (>120 μmol/L Phe) in the Czech Republic. It was not specified whether the patient's genotype was homozygous or compound heterozygous for the variant. PMID: 23357515

PVS1

This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. Loss of function is a known mechanism of disease: 175 pathogenic null variants were reported in ClinVar for this gene across 13 different exons, 22 of which are in exon 6.

PM2

This variant is absent from population databases gnomAD, 1000 Genomes and ESP.

Approved on: 2020-11-24

Published on: 2021-01-15

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