Submissions for variant NM_000277.3(PAH):c.529G>A (p.Val177Met)

dbSNP: rs199475602

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000534379	SCV000886567	pathogenic	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID: 12501224 It has been detected with known pathogenic variants R408W (PMID: 12501224), and IVS12+1G>A (PMID: 23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534379	SCV000629200	pathogenic	Phenylketonuria	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 177 of the PAH protein (p.Val177Met). This variant is present in population databases (rs199475602, gnomAD 0.003%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia (PMID: 12501224, 17096675, 23430547, 23500595, 23764561, 27121329). ClinVar contains an entry for this variant (Variation ID: 102726). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.Val177 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659548, 21445337, 22526846). 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	RCV000589313	SCV000696455	pathogenic	Hyperphenylalaninemia	2016-08-04	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.529G>A (p.Val177Met) variant is located in the catalytic domain and causes a missense change involving a conserved nucleotide with 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120722 (1/60361), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals as a compound heterozygote, predominanlty in patients with mild hyperphenylalaninemia. A database cites the variant, however, with no classification being provided. Furthermore, another variant at this position, V177L (c.529G>C), has been reported as a pathogenic variant, as well. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
GeneDx	RCV000088975	SCV001801004	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh MR et al., 2008; Leuret O et al., 2012); This variant is associated with the following publications: (PMID: 12649065, 23500595, 12501224, 17924342, 23430547, 17096675, 23764561, 34426522, 31589614, 35405047, 17935162, 22388642, 27121329)
Genome-Nilou Lab	RCV000534379	SCV001810545	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000534379	SCV002801585	pathogenic	Phenylketonuria	2022-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000534379	SCV004201332	pathogenic	Phenylketonuria	2024-03-18	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000534379	SCV005051897	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088975	SCV005624693	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	The PAH c.529G>A (p.Val177Met) variant has been reported in the published literature as heterozygous or compound heterozygous along with another pathogenic variant in several individuals with mild Hyperphenylalaninemia (PMID: 35405047 (2022), 27121329 (2016), 23430547 (2013), 23500595 (2013), 23764561 (2013), 17096675 (2007), 12501224 (2002)). Another variant at the same amino acid position, c.529G>C (p.Val177Leu), has been reported in individuals with Hyperphenylalaninemia (PMID: 8659548 (1996), 22526846 (2013)) and described as pathogenic in online databases (ClinVar https://www.ncbi.nlm.nih.gov/clinvar). The frequency of this variant in the general population, 0.000031 (4/128966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088975	SCV000119578	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000534379	SCV000795816	likely pathogenic	Phenylketonuria	2017-11-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000534379	SCV001455094	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905086	SCV004726018	pathogenic	PAH-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The PAH c.529G>A variant is predicted to result in the amino acid substitution p.Val177Met. This variant has been reported in individuals with mild hyperphenylalaninemia (see for example Muntau et al. 2002. PubMed ID: 12501224; Daniele et al. 2006. PubMed ID: 17096675; Djordjevic et al. 2012. PubMed ID: 23430547; Polak et al. 2013. PubMed ID: 23764561; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329). Alternative nucleotide substitutions at this amino acid position, including c.529G>C (p.Val177Leu) and c.530T>C (p.Val177Ala), have also been reported to be causative for phenylalanine hydroxylase deficiency (p.Val177Leu in Guldberg et al. 1996. PubMed ID: 8659548 and p.Val177Ala in Jennings et al. 2000. PubMed ID: 10980574). In ClinVar, the c.529G>A (p.Val177Met) variant is interpreted as pathogenic. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.