ClinVar Miner

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

dbSNP: 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000796569 SCV000936088 likely pathogenic Phenylketonuria 2021-12-02 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 625291). This missense change has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 31332730, 31355225, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 435 of the PAH protein (p.Asp435Val).
Center for Molecular Medicine, Children’s Hospital of Fudan University RCV000796569 SCV000893132 pathogenic Phenylketonuria 2019-03-08 no assertion criteria provided clinical testing

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