Submissions for variant NM_000277.3(PAH):c.493G>C (p.Ala165Pro)

dbSNP: rs199475626

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672775	SCV001146732	uncertain significance	Phenylketonuria	2019-04-07	reviewed by expert panel	curation	The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID: 26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.
Counsyl	RCV000672775	SCV000797914	uncertain significance	Phenylketonuria	2018-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672775	SCV001586744	pathogenic	Phenylketonuria	2021-12-24	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs199475626, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylkeonuria (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 102701). 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. This variant disrupts the p.Ala165 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26666653; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 165 of the PAH protein (p.Ala165Pro).
3billion, Medical Genetics	RCV000672775	SCV002058464	likely pathogenic	Phenylketonuria	2022-01-03	criteria provided, single submitter	clinical testing	The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102700,VCV000805818, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088949	SCV000119550	not provided	not provided		no assertion provided	not provided