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

CA1139532470

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 45056d89-5ee5-4a19-8f79-b363624d6a97

HGVS expressions

NM_001354304.2:c.463del

NC_000012.12:g.102866643del

CM000674.2:g.102866643del

NC_000012.11:g.103260421del

CM000674.1:g.103260421del

NC_000012.10:g.101784551del

NG_008690.1:g.55961del

NG_008690.2:g.96769del

NM_000277.1:c.463del

NM_000277.2:c.463del

NM_001354304.1:c.463del

NM_000277.3:c.463del

ENST00000307000.7:c.448del

ENST00000549111.5:n.559del

ENST00000551988.5:n.530+10820del

ENST00000553106.5:c.463del

Pathogenic

PM2 PVS1 PP4

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.463del (p.Arg155ValfsTer?) in PAH was reported in at least 1 Han Chinese patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 28982351), although a defect in BH4 metabolism was excluded by urinary pterin analysis only. This is a frameshift variant in exon 5 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.

PM2

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

PVS1

PVS1_met: This is a frameshift variant in exon 5 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, 7 of which are in exon 5.

PP4

PP4_met: This variant was documented in at least 1 patient with PAH deficiency (PMID: 28982351). 28982351, Liu - This variant was documented in at least 1 Han Chinese patient (paper did not mention how many patients had this variant) with PAH deficiency. Phenylalanine plasma concentrations >120 μmol/ L were reported for all subjects. Patients with BH4 cofactor deficiency were excluded but only urinary pterin analysis was mentioned as a method of exclusion.

PubMed:28982351

Approved on: 2020-10-15

Published on: 2020-10-15

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