Submissions for variant NM_000277.3(PAH):c.1183G>C (p.Ala395Pro)

gnomAD frequency: 0.00001  dbSNP: rs62516103

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781679	SCV000919911	pathogenic	Phenylketonuria	2017-12-07	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.1183G>C (p.Ala395Pro) variant involves the alteration of a conserved nucleotide located in Catalytic domain (Zurfluh_2008). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/246070 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in multiple PKU patients and shown to lead to decreased residual activity (Zurfluh_2008, Dobrowolski_2007, Lassker_2002). Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781679	SCV000948126	pathogenic	Phenylketonuria	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 395 of the PAH protein (p.Ala395Pro). This variant is present in population databases (rs62516103, gnomAD 0.004%). This missense change has been observed in individual(s) with classic PKU (PMID: 7726156, 11999982, 17502162, 22841515). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102547). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000781679	SCV004209640	pathogenic	Phenylketonuria	2023-07-11	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088781	SCV000119368	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000781679	SCV002088624	pathogenic	Phenylketonuria	2020-08-17	no assertion criteria provided	clinical testing