Submissions for variant NM_000277.3(PAH):c.965C>G (p.Ala322Gly)

gnomAD frequency: 0.00003  dbSNP: rs62514958

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000675108	SCV001146699	likely pathogenic	Phenylketonuria	2019-09-27	reviewed by expert panel	curation	The c.965C>G (p.Ala322Gly) variant in PAH has been reported in 4 individuals with mild hyperphenylalaninemia (BH4 deficiency not excluded). (PP4; PMID: 12501224). This variant has an allele frequency higher than the PAH VCEP PM2 threshold (MAF=0.00044). This variant was detected with p.R408W in 3 individuals (Pathogenic in ClinVar) and with p.R252W in 1 individual (PM3_strong; PMID: 12501224). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM3-strong, PP3.
Counsyl	RCV000675108	SCV000800656	uncertain significance	Phenylketonuria	2018-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675108	SCV000834485	pathogenic	Phenylketonuria	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 322 of the PAH protein (p.Ala322Gly). This variant is present in population databases (rs62514958, gnomAD 0.04%). This missense change has been observed in individual(s) with PKU, MHP, or non-PKU HPA (PMID: 1301200, 10234516, 21871829, 27469133). 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: 616). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 1301200, 9450897). This variant disrupts the p.Ala322 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 22526846), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251845	SCV002523149	likely pathogenic	See cases	2021-05-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM3, PP3, PP4
Baylor Genetics	RCV000675108	SCV004209616	pathogenic	Phenylketonuria	2024-02-28	criteria provided, single submitter	clinical testing
OMIM	RCV000000647	SCV000020797	pathogenic	Mild non-PKU hyperphenylalanemia	1992-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089177	SCV000119792	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000675108	SCV001463127	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing