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

CA16020857

619150 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ff16e9ce-c14a-43a3-9502-03a9763729f0

HGVS expressions

NM_000277.1:c.788T>C

NC_000012.12:g.102852869A>G

CM000674.2:g.102852869A>G

NC_000012.11:g.103246647A>G

CM000674.1:g.103246647A>G

NC_000012.10:g.101770777A>G

NG_008690.1:g.69734T>C

NG_008690.2:g.110542T>C

NM_000277.2:c.788T>C

NM_001354304.1:c.788T>C

NM_000277.3:c.788T>C

ENST00000307000.7:c.773T>C

ENST00000549247.6:n.547T>C

ENST00000553106.5:c.788T>C

Pathogenic

PS3 PP3 PP4 PM2 PM3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.788T>C (p.Phe263Ser) variant in PAH has been reported in 1 patient with hyperphenylalaninemia (BH4 deficiency not excluded) and was detected with known pathogenic variant c.1066-11G>A (PP4, PM3; PMID: 23357515). This variant is absent in population databases (PM2). This variant has 4% enzyme activity (PS3; PMID:20179079). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP3, PP4.

PS3

COS-7 cells expressing a recombinant PAH protein carrying p.Phe263Ser show almost no PAH activity (4+/-17 % of w.t.). PMID: 20179079

mouse model of HPA with in vitro analysis of murine recombinant PAH proteins; the Pahenu mouse carries p.Phe263Ser on both alleles and is characterized by the classical PKU phenotype, and COS-7 cells expressing a recombinant murine protein carrying p.Phe263Ser show almost no PAH activity (4+/-17 % of w.t.). PubMed:20179079

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster

PP4

F263 seen on 1 allele in a Czech HPA patient. PMID: 23357515

665 unrelated Czech HPA patients. F263S seen on 1 allele. PubMed:23357515

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

Detected with c.1066-11G>A. PMID: 23357515

Based on our analysis, we predict that p.(Phe263Ser) causes significant impairment of the protein structure and function, and that patients carrying this mutation have the classical PKU phenotype (like our patient with the genotype p.[Phe263Ser];[c.1066-11 G > A]). PubMed:23357515

Approved on: 2018-12-10

Published on: 2019-04-05

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