Submissions for variant NM_000277.3(PAH):c.856G>A (p.Glu286Lys)

dbSNP: rs62508739

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000758134	SCV000886620	pathogenic	Phenylketonuria	2018-12-09	reviewed by expert panel	curation	The c.856G>A (p.Glu286Lys) variant in PAH is present with low frequency in population databases (1.2e-4), and is predicted to be deleterious using in silico algorithms. It has been identified in trans with pathogenic variants in two independent patients (R243Q, R241C), and has been identified in a patients with Phenylketonuria in which a defect in BH4 metabolism has been excluded (PMID: 14722928, 24401910). Enzyme activity has been measured as 1% of wild type controls (BioPKU). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PS3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758134	SCV002111505	pathogenic	Phenylketonuria	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 286 of the PAH protein (p.Glu286Lys). This variant is present in population databases (rs62508739, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 14722928, 29499199). ClinVar contains an entry for this variant (Variation ID: 102880). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000758134	SCV002819480	pathogenic	Phenylketonuria	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.856G>A (p.Glu286Lys) 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 1.2e-05 in 250962 control chromosomes. c.856G>A has been reported in the literature in multiple individuals affected with classical PKU, mild PKU and MHP (eg. Liang_2014, Wang_2018, etc). These data indicate that the variant is very likely to be associated with disease. PAH activity from COS-1 cells transfected with the showed the variant to have <10% PAH activity compared to wild-type (Liang_2014). One diagnostic clinical lab and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000758134	SCV004209597	pathogenic	Phenylketonuria	2023-11-27	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089141	SCV000119752	not provided	not provided		no assertion provided	not provided