Submissions for variant NM_000277.3(PAH):c.1156T>G (p.Tyr386Asp)

dbSNP: rs199475691

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001239036	SCV002540159	likely pathogenic	Phenylketonuria	2022-06-24	reviewed by expert panel	curation	The c.1156T>G (p.Tyr386Asp) variant in PAH has been reported in 1 female, Italian patient - type of PKU not specified, serum Phe = 822umol/L; BH4 responsiveness was not specified (PMID: 23430918; PP4). This variant has been detected with R158Q - reported as pathogenic in ClinVar (VarID:587), 14 submitters, phase unknown - 0.5 points (PMID: 23430918; PM3_Supporting). Another missense change at the same amino is pathogenic (p.Tyr386Cys). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.977 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3, PP4, PM3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239036	SCV001411881	likely pathogenic	Phenylketonuria	2019-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with aspartic acid at codon 386 of the PAH protein (p.Tyr386Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with a pathogenic PAH variant in individuals affected with phenylketonuria or hyperphenylalaninemia (PMID: 23430918, Invitae). ClinVar contains an entry for this variant (Variation ID: 102537). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr386 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 16765994, 24368688, 23430918, 24350308, 16198137, 22841515), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088770	SCV000119355	not provided	not provided		no assertion provided	not provided