Submissions for variant NM_000277.3(PAH):c.776C>T (p.Ala259Val)

gnomAD frequency: 0.00001  dbSNP: rs118203921

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000000633	SCV000486832	likely pathogenic	Phenylketonuria	2016-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000633	SCV000951041	pathogenic	Phenylketonuria	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the PAH protein (p.Ala259Val). This variant is present in population databases (rs118203921, gnomAD 0.007%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2035532, 18299955, 26666653). ClinVar contains an entry for this variant (Variation ID: 602). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8304187, 9799096, 10479481). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000633	SCV004030153	pathogenic	Phenylketonuria	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: PAH c.776C>T (p.Ala259Val) 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 8e-06 in 251340 control chromosomes (gnomAD). c.776C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Koch_1997, Benit_1999, Jeannesson-Thivisol_2015). 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 and found the variant results in <5% of normal activity (e.g. Benit_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10479481, 26666653, 9169088). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000000633	SCV004209712	pathogenic	Phenylketonuria	2023-01-10	criteria provided, single submitter	clinical testing
OMIM	RCV000000633	SCV000020783	pathogenic	Phenylketonuria	1991-06-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089089	SCV000119695	not provided	not provided		no assertion provided	not provided