ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1304A>T (p.Asp435Val) (rs1592945394)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000796569 SCV001370821 likely pathogenic Phenylketonuria 2020-04-10 reviewed by expert panel curation The c.1304A>T (p.Asp435Val) variant in PAH has been reported in a Uygur patient with moderate PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 31355225). This variant was detected with p.Ala434Asp (Likely pathogenic in ClinVar) (PM3; PMID: 31355225). The variant is absent from population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate.
Invitae RCV000796569 SCV000936088 uncertain significance Phenylketonuria 2018-08-04 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 435 of the PAH protein (p.Asp435Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PAH-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan University RCV000796569 SCV000893132 pathogenic Phenylketonuria 2019-03-08 no assertion criteria provided clinical testing

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