Submissions for variant NM_000277.3(PAH):c.1028A>G (p.Tyr343Cys) (rs62507265)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000088708	SCV000582433	likely pathogenic	not provided	2015-10-01	criteria provided, single submitter	clinical testing	The Y343C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y343C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (Y343D and Y343F) and in nearby residues (D388Y, I340T, K341/R/T, A342T/P, G344R/S/D/V, A345S/T, G346R/E, L347F, L348V) have been reported in the Human Gene Mutation Database in association with phenylketonuria (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret the Y343C variant to be likely pathogenic; however, the possibility that it is benign cannot be excluded.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088708	SCV000119288	not provided	not provided		no assertion provided	not provided