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

dbSNP: rs62508694

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000340479	SCV004015306	pathogenic	Phenylketonuria	2020-06-26	reviewed by expert panel	curation	The c.733G>C (p.Val245Leu) variant in PAH has been reported in 3 individuals with PAH deficiency, detected with pathogenic variants p.R408Q and p.A104D (PMID: 8659548, 24368688). This variant has an extremely low allele frequency (0.000008972) in gnomAD. This variant has 13% enzyme activity (PMID: 11161839). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PS3, PM2, PM3, PP3.
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000340479	SCV001213578	pathogenic	Phenylketonuria	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 245 of the PAH protein (p.Val245Leu). This variant is present in population databases (rs62508694, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8659548, 22841515, 24368688, 24667082). ClinVar contains an entry for this variant (Variation ID: 102810). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000340479	SCV001363420	pathogenic	Phenylketonuria	2022-02-03	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 4e-06 in 251200 control chromosomes. c.733G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, 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 PAH enzyme activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000089063	SCV001820231	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Functional analysis found that V245L is associated with 7-15% enzyme activity compared to wild-type and is associated with a classic PKU phenotype (Gjetting et al., 2001; Pey et al., 2007).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9012412, 8659548, 25596310, 11161839, 24368688, 22841515, 17924342, 24667082, 24296287, 8088845, 35339094, 26803807)
Baylor Genetics	RCV000340479	SCV004209655	pathogenic	Phenylketonuria	2023-12-18	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089063	SCV000119669	not provided	not provided		no assertion provided	not provided