Submissions for variant NM_000277.3(PAH):c.472C>T (p.Arg158Trp)

gnomAD frequency: 0.00004  dbSNP: rs75166491

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000409986	SCV000852152	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).
GeneDx	RCV000088941	SCV000581901	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Reported homozygous in an individual with mild-moderate PKU (Jeannesson-Thivisol et al., 2015); however, this variant has also been identified in individuals with classic PKU (Yamashita et al., 1992; Bashyam et al., 2014; Jeannesson-Thivisol et al., 2015; Danecka et al., 2015); Published functional studies demonstrate p.(R158W) results in significantly reduced residual activity compared to wildtype (Danecka et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25750018, 34828281, 29413232, 25087612, 25596310, 1307609, 26666653, 24130151, 29499199, 30747360, 30275481, 32668217, 32778825, 33375644, 17935162, 17924342)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409986	SCV000818627	pathogenic	Phenylketonuria	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 158 of the PAH protein (p.Arg158Trp). This variant is present in population databases (rs75166491, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 10356314, 14681498, 19609714, 20082265, 23430918, 24130151, 24941924, 25894915, 26666653). ClinVar contains an entry for this variant (Variation ID: 102693). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg158 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 10479481, 23500595, 24368688, 25596310). 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	RCV000409986	SCV002571860	pathogenic	Phenylketonuria	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: PAH c.472C>T (p.Arg158Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of 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 2.8e-05 in 251352 control chromosomes (gnomAD). c.472C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Shintaku_2003, Santos__2010, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in <10% of normal activity (Danecka_2015). In addition, another variant (p.Arg158Gln) at the same residue was found in many individuals affected Phenylketonuria and has been classified as pathogenic at our laboratory, indicating the arginine residue is critical for protein function. Five ClinVar submitters (evaluation after 2014, including one expert panel, ClinGen PAH Variant Curation Expert Panel) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000409986	SCV003822270	pathogenic	Phenylketonuria	2022-01-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000409986	SCV004047838	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	The missense variant c.472C>T (p.Arg158Trp) in PAH gene has been reported as homozygous or in combination with another PAH variant in multiple individuals affected with phenylketonuria (Santos LL et.al.,2010). Functional analysis found that R158W is associated with 1.8% residual enzyme activity compared to wild type (Danecka et al.,2015). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg158Trp variant is reported with allele frequency 0.003% in gnomAD exomes and novel in 1000 Genomes. The amino acid Arg at position 158 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg158Trp in PAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Baylor Genetics	RCV000409986	SCV004201369	pathogenic	Phenylketonuria	2024-03-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088941	SCV005624692	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	The PAH c.472C>T (p.Arg158Trp) variant has been reported in the published literature in individuals with phenylketonuria, whom were either compound heterozygous or homozygous for the variant (PMIDs: 23430918 (2012), 20082265 (2010), 10394930 (1999), 9634518 (1998)). Functional evidence suggests that this variant may impact protein function ( Phenylalanine Hydroxylase Gene Locus-Specific Database (http://www.biopku.org/)). 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	RCV000088941	SCV000119541	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000409986	SCV000485294	pathogenic	Phenylketonuria	2016-01-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000409986	SCV001455103	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing