ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1184C>G (p.Ala395Gly) (rs62508736)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410586 SCV000485283 likely pathogenic Phenylketonuria 2016-07-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000410586 SCV000917929 pathogenic Phenylketonuria 2018-11-16 criteria provided, single submitter clinical testing Variant summary: PAH c.1184C>G (p.Ala395Gly) results in a non-conservative amino acid change located in the C-terminal domain, containing the catalytic domain and the coiled-coil C-terminal oligomerization motif (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276980 control chromosomes (gnomAD). c.1184C>G has been reported in the literature in a homozygous individual affected with mild Hyperphenylalaninemia (MHP) (Bercovich 2008) and multiple compound heterozugous individuals affected with MHP or mild to moderate PKU phenotype (Guttler 1999, Bercovich 2008, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease; however, in general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000410586 SCV001220571 pathogenic Phenylketonuria 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 395 of the PAH protein (p.Ala395Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs62508736, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another PAH variant in several individuals affected with hyperphenylalaninemia or phenylketonuria (PMID: 18299955, 27121329, 24368688). ClinVar contains an entry for this variant (Variation ID: 102549). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ala395 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11999982, 7726156, 22841515, 17502162, 11161839). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088783 SCV000119370 not provided not provided no assertion provided not provided
Division of Human Genetics,Children's Hospital of Philadelphia RCV000410586 SCV000536786 likely pathogenic Phenylketonuria 2016-04-28 no assertion criteria provided research

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