Submissions for variant NM_000277.3(PAH):c.386A>G (p.Asp129Gly)

gnomAD frequency: 0.00001  dbSNP: rs199475623

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672629	SCV001146722	likely pathogenic	Phenylketonuria	2019-04-05	reviewed by expert panel	curation	The c.386A>G (p.Asp129Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8981952). This variant has extremely low frequency in gnomAD (MAF: 0.00001; PM2). This variant was detected in trans with known pathogenic variant c.1066-11G>A (PM3; PMID: 27121329). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Counsyl	RCV000672629	SCV000797753	likely pathogenic	Phenylketonuria	2018-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672629	SCV001218441	pathogenic	Phenylketonuria	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 129 of the PAH protein (p.Asp129Gly). This variant is present in population databases (rs199475623, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9359039). ClinVar contains an entry for this variant (Variation ID: 102661). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 23559577). This variant disrupts the p.Asp129 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26542770; 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672629	SCV001774640	pathogenic	Phenylketonuria	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.386A>G (p.Asp129Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes. c.386A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Reblova_2013, Anjema_2013, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000672629	SCV004209643	pathogenic	Phenylketonuria	2023-11-27	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088908	SCV000119506	not provided	not provided		no assertion provided	not provided