Submissions for variant NM_000277.3(PAH):c.193A>G (p.Ile65Val)

gnomAD frequency: 0.00001  dbSNP: rs199475643

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000803656	SCV002540168	pathogenic	Phenylketonuria	2022-06-28	reviewed by expert panel	curation	The c.193A>G (p.Ile65Val) variant in PAH has been reported in multiple individuals with mild PKU and mild hyperphenylalaninaemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 12501224). This variant is at extremely low frequency: gnomAD MAF 0.00003 (PM2). This variant was detected with multiple pathogenic variants: p.R261Q, IVS12+1G>A (PMID: 12501224); c.168+5G>C (PMID: 22526846); p.Y386C (PMID: 26210745); p.EX6-96A>G (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect (PP3). Another missense change at the same amino acid residue is pathogenic (p.Ile65Thr). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PM5, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803656	SCV000943538	pathogenic	Phenylketonuria	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the PAH protein (p.Ile65Val). This variant is present in population databases (rs199475643, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 12501224, 12655553, 17935162, 22526846, 23357515, 23792259, 26210745, 26503515; Invitae). ClinVar contains an entry for this variant (Variation ID: 102622). 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%. This variant disrupts the p.Ile65 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12655546, 23500595, 25596310; 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.
Fulgent Genetics, Fulgent Genetics	RCV000803656	SCV002811564	pathogenic	Phenylketonuria	2022-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000803656	SCV004209579	pathogenic	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088864	SCV000119459	not provided	not provided		no assertion provided	not provided