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]

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CA16020843

619163 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b990f0f7-2c1b-428d-bfec-28ed05f717f4

Approved on: 2018-12-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.697T>A

NC_000012.12:g.102855145A>T

CM000674.2:g.102855145A>T

NC_000012.11:g.103248923A>T

CM000674.1:g.103248923A>T

NC_000012.10:g.101773053A>T

NG_008690.1:g.67458T>A

NG_008690.2:g.108266T>A

NM_000277.2:c.697T>A

NM_001354304.1:c.697T>A

NM_000277.3:c.697T>A

ENST00000307000.7:c.682T>A

ENST00000549111.5:n.793T>A

ENST00000553106.5:c.697T>A

Pathogenic

PP3 PS3 PM2 PM3_Strong PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.697T>A (p.Phe233Ile) variant in PAH has been reported in 2 unrelated patients with PKU (BH4 deficiency excluded) and was detected with known pathogenic variants p.R408W and p.V245A. (PP4_Moderate, PM3_Strong; PMID: 23764561). This variant is absent in population databases (PM2). This variant showed no specific activity in functional assay and no response to chaperone co-expression (PS3; PMID: 28653649). Computational prediction tools and conservation analysis suggest 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: PP4_Moderate, PS3, PM3_strong, PM2, PP3.

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.92

PS3

Showed no specific activity in functional assay and no response to chaperone co-expression. PMID: 28653649

In this study, in silico prediction and in vitro prokaryotic and eukaryotic expression systems were used to functionally characterize five PAH missense variants (including p.F233I). p.F233I was classified as deleterious mutations since it showed no specific activity in functional assay and no response to chaperone co-expression. Protein levels of the PAH variant was very low when expressed in HepG2 cells. PubMed:28653649

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3_Strong

p.F233I was detected in two apparently unrelated patients in compound heterozygosity with p.R408W (VarID 577, Pathogenic) and p.V245A (Pathogenic) PMID: 23764561

Mutation p.F233I was detected in two apparently unrelated patients in compound heterozygosity with p.R408W (VarID 577, Pathogenic) and p.V245A (Pathogenic) respectively. PubMed:23764561

PP4_Moderate

p.F233I was detected in two unrelated PKU patients. BH4 deficiency was excluded. PMID: 23764561

We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 135 Slovak PKU families. We identified the novel missense mutation: p.F233I. Patients with BH4 deficiency were excluded from molecular analysis. PubMed:23764561

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