ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1157A>G (p.Tyr386Cys) (rs62516141)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169306 SCV000220627 likely pathogenic Phenylketonuria 2014-08-22 criteria provided, single submitter literature only
GeneDx RCV000088771 SCV000239087 pathogenic not provided 2015-05-26 criteria provided, single submitter clinical testing The Y386C missense mutation in the PAH gene has been reported as a pathogenic mutation in the PAH Consortium database. The variant is found in PAH panel(s).
Invitae RCV000169306 SCV000754086 pathogenic Phenylketonuria 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 386 of the PAH protein (p.Tyr386Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another PAH variant in individuals affected with phenylketonuria or hyperphenylalaninemia (PMID:16765994, 24368688, 23430918, 24350308. 16198137, 22841515). ClinVar contains an entry for this variant (Variation ID: 102538). 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. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169306 SCV000917928 pathogenic Phenylketonuria 2018-10-26 criteria provided, single submitter clinical testing Variant summary: PAH c.1157A>G (p.Tyr386Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (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 2e-05 in 246044 control chromosomes (gnomAD). c.1157A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Bayat_2016, Trunzo_2015, Ho_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088771 SCV000119356 not provided not provided no assertion provided not provided

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