ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.733G>C (p.Val245Leu) (rs62508694)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089063 SCV000331008 pathogenic not provided 2016-07-08 criteria provided, single submitter clinical testing
Counsyl RCV000340479 SCV000797092 likely pathogenic Phenylketonuria 2018-01-19 criteria provided, single submitter clinical testing
Invitae RCV000340479 SCV001213578 pathogenic Phenylketonuria 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 245 of the PAH protein (p.Val245Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs62508694, ExAC 0.002%). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 8659548, 22841515, 24667082, 24368688). ClinVar contains an entry for this variant (Variation ID: 102810). This variant has been reported to affect PAH protein function (PMID: 17924342, 11161839). This variant disrupts the p.Val245 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8088845, 24296287, 25596310, 26803807). 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.
Integrated Genetics/Laboratory Corporation of America RCV000340479 SCV001363420 pathogenic Phenylketonuria 2019-03-11 criteria provided, single submitter clinical testing Variant summary: PAH c.733G>C (p.Val245Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245968 control chromosomes (gnomAD). c.733G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Guldberg_1996, Quirk_2012, Tyfield_1997, Ho_2014, Grange_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Gjetting_2001). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as likely pathogenic and onces as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089063 SCV000119669 not provided not provided no assertion provided not provided

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