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

CA16020829

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bbfd87fe-4735-4834-a1c7-78681e0e1110

HGVS expressions

NM_001354304.2:c.607dup

NC_000012.12:g.102855236dup

CM000674.2:g.102855236dup

NC_000012.11:g.103249014dup

CM000674.1:g.103249014dup

NC_000012.10:g.101773144dup

NG_008690.1:g.67368dup

NG_008690.2:g.108176dup

NM_000277.1:c.607dup

NM_000277.2:c.607dup

NM_001354304.1:c.607dup

NM_000277.3:c.607dup

ENST00000307000.7:c.592dup

ENST00000549111.5:n.703dup

ENST00000553106.5:c.607dup

Pathogenic

PVS1 PP4 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This variant c.607dup (p.Cys203LeufsTer3) in PAH was reported in at least 1 Czech patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This is a frameshift variant in exon 6 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, 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. This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.

PVS1

PVS1_met: This is a frameshift variant in exon 6 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, 22 of which are in exon 6.

PP4

PP4_met: This variant was documented in at least 1 patient with HPA (PMID: 23357515). 23357515, Réblová - This variant was documented in at least 1 Czech patient (paper did not mention how many patients had this variant) with HPA. The paper defined HPA in their intro: "HPA patients can be classified based on their off-diet diagnostic plasma Phe levels as classical PKU (Phe above 1200 μmol/L), mild PKU (Phe between 600 and 1200 μmol/L) or non-PKU HPA (Phe between 120 and 600 μmol/L)."

PubMed:23357515

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

Approved on: 2020-10-15

Published on: 2020-10-15

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