Submissions for variant NM_000277.3(PAH):c.281T>G (p.Ile94Ser)

gnomAD frequency: 0.00001  dbSNP: rs62508677

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673537	SCV000798749	uncertain significance	Phenylketonuria	2018-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV000673537	SCV004296185	pathogenic	Phenylketonuria	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 94 of the PAH protein (p.Ile94Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PKU) (PMID: 16198137, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102644). 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 not expected to disrupt PAH protein function. This variant disrupts the p.Ile94 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217; BIOPKU http://www.biopku.org), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088889	SCV000119486	not provided	not provided		no assertion provided	not provided