Submissions for variant NM_000277.3(PAH):c.839A>G (p.Glu280Gly)

dbSNP: rs62508734

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632877	SCV000754074	pathogenic	Phenylketonuria	2017-10-12	criteria provided, single submitter	clinical testing	A different missense substitution at this codon (p.Glu208Lys) has been determined to be pathogenic (PMID: 12655546, 17935162, 23500595, 2564729, 2014036, 12655546, 17935162, 21953985, 2014036, Invitae). This suggests that the glutamic acid residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change impairs PAH enzyme activity in vitro (PMID: 18247293). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with PKU (Invitae). In addition, this variant has been reported in combination with another PAH variant in an individual affected with PKU (PMID: 18247293). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 102866). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 280 of the PAH protein (p.Glu280Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089127	SCV000119736	not provided	not provided		no assertion provided	not provided