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

CA386295265

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e05cd454-2980-40bd-a3f1-208774b09ca8

HGVS expressions

NM_001354304.2:c.804C>A

NM_000277.1:c.804C>A

NM_000277.2:c.804C>A

NM_001354304.1:c.804C>A

NM_000277.3:c.804C>A

ENST00000307000.7:c.789C>A

ENST00000549247.6:n.563C>A

ENST00000553106.5:c.804C>A

NC_000012.12:g.102852853G>T

CM000674.2:g.102852853G>T

NC_000012.11:g.103246631G>T

CM000674.1:g.103246631G>T

NC_000012.10:g.101770761G>T

NG_008690.1:g.69750C>A

NG_008690.2:g.110558C>A

Pathogenic

PP4 PM2 PM3 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.804C>A (p.Tyr268Ter) variant in PAH was observed in a patient with classical PKU detected with pathogenic variant p.Arg243Gln (PMID: 28982351). This variant is absent from controls in population databases. This is a nonsense variant in exon 7 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, and PP4.

PP4

Identified in a patient with classical PKU (Phe = 1500 µmol/L). Patients with BH4 cofactor deficiency were ruled out using urinary pterin analysis. There is no mention of DHPR being assessed. PMID: 28982351

PubMed:28982351

PM2

This variant is absent from controls in ExAC and 1000 Genomes.

PM3

[p.Arg243Gln,p.Tyr268*]. Segregation analysis was done. PMID: 28982351

PVS1

This is a nonsense variant in exon 7 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA 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 reported in Clinvar across 13 different exons, 19 of which are in exon 7.

Approved on: 2020-10-15

Published on: 2020-10-15

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