Submissions for variant NM_000277.3(PAH):c.734T>A (p.Val245Glu)

dbSNP: rs76212747

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632879	SCV000754079	pathogenic	Phenylketonuria	2023-09-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with phenylketonuria (PMID: 15159646). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 245 of the PAH protein (p.Val245Glu). This variant is present in population databases (rs76212747, gnomAD 0.005%). ClinVar contains an entry for this variant (Variation ID: 102811). 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). 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089064	SCV000119670	not provided	not provided		no assertion provided	not provided