Submissions for variant NM_000277.3(PAH):c.473G>A (p.Arg158Gln)

gnomAD frequency: 0.00007  dbSNP: rs5030843

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000618	SCV000852101	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). 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: (PS3, PP3, PP4_Moderate, PM3_VeryStrong).
Eurofins Ntd Llc (ga)	RCV000078522	SCV000110378	pathogenic	not provided	2016-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000078522	SCV000239054	pathogenic	not provided	2020-05-04	criteria provided, single submitter	clinical testing	Associated with significantly reduced enzyme activity compared to wild type (Steventon et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; BH4 responsiveness has been inconsistent in patients with R158Q (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 26210745, 27264808, 25087612, 30963030, 31355225, 17924342, 22975760, 12655546, 2014036, 21953985, 19036622, 2606484, 17935162, 28754886, 29288420, 29111448, 28956315, 29316886, 28676969, 23500595, 25750018, 26803807, 29499199, 30747360, 31589614, 33101986, 8188310)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078522	SCV000601714	pathogenic	not provided	2021-10-21	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals affected by Phenylketonuria (PKU) (PMIDs: 2606484 (1989), 12655546 (2003), 30747360 (2019), and 31355225 (2019)). Functional studies show that this variant is predicted to negatively impact protein function (PMIDs: 12655546 (2003), 17935162 (2008), 19036622 (2009), 21953985 (2012), and 25750018 (2015)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000000618	SCV000611233	pathogenic	Phenylketonuria	2022-01-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000618	SCV000629193	pathogenic	Phenylketonuria	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 158 of the PAH protein (p.Arg158Gln). This variant is present in population databases (rs5030843, gnomAD 0.02%). This missense change has been observed in individuals with PKU (PMID: 2014036, 10479481, 23500595, 24368688, 25596310). ClinVar contains an entry for this variant (Variation ID: 587). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 14654665, 19036622). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000618	SCV000696450	pathogenic	Phenylketonuria	2016-07-28	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.473G>A (p.Arg158Gln) variant involves the alteration of a conserved nucleotide. The affected amino acid, Arg158, is located in the Aromatic amino acid hydroxylase, C-terminal domain. 4/5 in silico tools predict a damaging outcome for this variant, and the residual activity from in vitro cell based assays was reported to be 10% of wild type activity (Zurfluh_HM_2008 and BIOPKU database). This variant was found in 12/121256 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in numerous patients with classic or moderate PKU. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000000618	SCV000746356	pathogenic	Phenylketonuria	2017-12-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000618	SCV001163725	pathogenic	Phenylketonuria	2024-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000000618	SCV001193837	pathogenic	Phenylketonuria	2019-12-09	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.473G>A(R158Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with classic or variant PKU. Sources cited for classification include the following: PMID 22513348, 2014036, 2606484, 12655546, 19036622, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.473G>A(R158Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000078522	SCV001501430	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000000618	SCV002058800	pathogenic	Phenylketonuria	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000587, PMID:2606484, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102693, PMID:1307609,NULL,32668217, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965, 3CNET: 0.983, PP3_P). A missense variant is a common mechanism associated with Hyperphenylalaninemia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000092, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078522	SCV002525810	pathogenic	not provided	2024-07-02	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PM3_very_strong, PM5, PS3
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000000618	SCV005397649	pathogenic	Phenylketonuria	2024-04-19	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 473 of the coding sequence of the PAH gene that results in an arginine to glutamine amino acid change at residue 158 of the phenylalanine hydroxylase protein. This residue falls in the catalytic domain of the protein which is important for the binding of iron, cofactor, and substrate (PMID: 23457044). This is a previously reported variant (ClinVar 587) that has been classified as pathogenic by an expert panel (ClinGen SCV000852101.4). This variant has been observed in individuals affected by phenylketonuria and hyperphenylalaninemia (PMID: 2014036, 23500595, 10479481, 24368688). This variant is present in 225 of 1613598 alleles (0.014%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Arg158 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant demonstrate significantly impaired enzymatic activity (PMID: 2014036, 19036622, 23500595). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP3, PP4, PS3
OMIM	RCV000000618	SCV000020768	pathogenic	Phenylketonuria	1989-12-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078522	SCV000119542	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000000618	SCV000324887	not provided	Phenylketonuria		no assertion provided	literature only
Natera, Inc.	RCV000000618	SCV001455102	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078522	SCV001930656	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078522	SCV001958602	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078522	SCV001970641	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415608	SCV004117444	pathogenic	PAH-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The PAH c.473G>A variant is predicted to result in the amino acid substitution p.Arg158Gln. This variant has been commonly observed in individuals with phenylalanine hydroxylase deficiency and is associated clinically with phenylketonuria (PKU) (e.g., Dworniczak et al. 1989. PubMedID: 2606484; Bénit et al. 1999. PubMed ID: 10479481; Couce et al. 2013. PubMed ID: 23500595; Ho et al. 2014. PubMed ID: 24368688; Danecka et al. 2015. PubMed ID: 25596310). In functional studies, p.Arg158Gln substitution has been reported to reduce enzyme activity to 10% or less relative to control (Zurflüh et al. 2008. PubMed ID: 17935162; Steventon et al. 2009. PubMed ID: 19036622). This substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162; Couce et al. 2013. PubMed ID: 23500595). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as by many other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/587/). Based on these observations, we also interpret this variant as pathogenic.
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000000618	SCV004800897	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing	PS3+PM3_VS+PP3+PP4_M