Submissions for variant NM_000277.3(PAH):c.838G>C (p.Glu280Gln)

dbSNP: rs62508698

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001857433	SCV002286727	likely pathogenic	Phenylketonuria	2023-07-31	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Glu280 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 2564729, 12655546, 17935162, 23500595). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 102864). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217; Invitae). This variant is present in population databases (rs62508698, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 280 of the PAH protein (p.Glu280Gln).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089125	SCV000119734	not provided	not provided		no assertion provided	not provided