Submissions for variant NM_000277.3(PAH):c.1028A>G (p.Tyr343Cys)

dbSNP: rs62507265

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000088708	SCV000582433	likely pathogenic	not provided	2015-10-01	criteria provided, single submitter	clinical testing	The Y343C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y343C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (Y343D and Y343F) and in nearby residues (D388Y, I340T, K341/R/T, A342T/P, G344R/S/D/V, A345S/T, G346R/E, L347F, L348V) have been reported in the Human Gene Mutation Database in association with phenylketonuria (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret the Y343C variant to be likely pathogenic; however, the possibility that it is benign cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194126	SCV001363416	pathogenic	Phenylketonuria	2019-02-04	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1028A>G (p.Tyr343Cys) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246022 control chromosomes (gnomAD). c.1028A>G has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, PKU). Based on the data provided by the BioPKU database, the variant was found in 7 patients with mild hyperphenylalaninaemia or mild PKU (Garbade 2018). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001194126	SCV002245607	pathogenic	Phenylketonuria	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 343 of the PAH protein (p.Tyr343Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of phenylketonuria (PMID: 19913839, 23690520, 23842451, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102477). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001194126	SCV004209601	pathogenic	Phenylketonuria	2023-09-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088708	SCV005624688	likely pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	The PAH c.1028A>G (p.Tyr343Cys) variant has been reported in the published literature in individuals with PAH-related conditions (PMIDs: 8268925 (1993), 11708866 (2001), 12655553 (2003), 19913839 (2010), 29997390 (2019), 33625639 (2021) and 35405047 (2022)) including homozygous (PMIDs: 28593914 (2017) and 30159852 (2018)) or compound heterozygous individuals (PMIDs: 23842451 (2013), 27623981 (2017)), 35281663 (2022), and 37509538 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088708	SCV000119288	not provided	not provided		no assertion provided	not provided