Submissions for variant NM_000277.3(PAH):c.737C>A (p.Ala246Asp)

dbSNP: rs199475610

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002259592	SCV002540123	uncertain significance	Phenylketonuria	2020-11-13	reviewed by expert panel	curation	The c.737C>A (p.Ala246Asp) variant in PAH has been reported in 2 patients with PKU (PMID: 9012412,12173030), detected with pathogenic variant p.R408W in one patient (PMID: 31623983). This variant is absent in population databases. A deleterious effect is predicted by multiple lines of computational evidence. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting.
GeneDx	RCV000089067	SCV000516538	pathogenic	not provided	2015-03-26	criteria provided, single submitter	clinical testing	The A246D missense variants in the PAH gene has been reported as a pathogenicvariant in the PAH Consortium database. The A246D substitution was reported in a patient withphenylketonuria (PKU) from Western Scotland (Tyfield et al., 1997). To our knowledge, information onthe phenotype of patients harboring the A246D variant has not been published. A246D is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties, and a missense variant at the same position(A246V) and in many nearby residues (R243L/Q, P244L, V245L/E/A, G247S/R/V/D, L248R/P,L249F/P/H) have been reported in the Human Gene Mutation Database in association with PKU (Stensonet al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpretA246D to be a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002259592	SCV003441156	pathogenic	Phenylketonuria	2023-01-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala246 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 102812). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 32668217; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 246 of the PAH protein (p.Ala246Asp).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089067	SCV000119673	not provided	not provided		no assertion provided	not provided