Submissions for variant NM_000277.3(PAH):c.782G>A (p.Arg261Gln)

gnomAD frequency: 0.00022  dbSNP: rs5030849

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000612	SCV000852142	pathogenic	Phenylketonuria	2018-08-13	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). 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: (PP3, PS3, PM3_VeryStrong, PP4_Moderate).
Eurofins Ntd Llc (ga)	RCV000078530	SCV000110386	pathogenic	not provided	2016-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000078530	SCV000239072	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 23559577, 19036622, 12655546, 10479481, 30747360, 26655635, 26759449, 26919687, 24401910, 25596310, 21953985, 2574153, 24296287, 26803807, 27682710, 11999982, 25750018, 27264808, 28676969, 22975760, 23500595, 9323556, 19194782, 29499199, 30037505, 27121329, 21527427, 8825928, 30963030, 31355225, 31028937, 30275481, 34426522, 31589614, 32905092, 33101986, 8188310, 32853555, 1915502, 1677425, 32778825, 33465300, 29288420, 8445616, 33375644, 17935162, 2014036, 8487271)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078530	SCV000281282	pathogenic	not provided	2014-12-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000000612	SCV000611234	pathogenic	Phenylketonuria	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000612	SCV000629215	pathogenic	Phenylketonuria	2025-01-29	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 261 of the PAH protein (p.Arg261Gln). This variant is present in population databases (rs5030849, gnomAD 0.04%). This missense change has been observed in individual(s) with PKU (PMID: 2574153, 16765994). ClinVar contains an entry for this variant (Variation ID: 582). 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: 10479481, 17935162, 25596310). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000612	SCV000696466	pathogenic	Phenylketonuria	2016-07-14	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.782G>A (p.Arg261Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. Arg261 is highly conserved across species and is located in the Aromatic amino acid hydroxylase, C-terminal of the Phenylalanine-4-hydroxylase protein.This variant was found in 33/121376 control chromosomes at a frequency of 0.0002719, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many PKU and HPA patients in homozygous or compound heterozygous state, and is considered a commonly known pathogenic PAH variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078530	SCV000888353	pathogenic	not provided	2019-09-13	criteria provided, single submitter	clinical testing	Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Mendelics	RCV000000612	SCV001138801	pathogenic	Phenylketonuria	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000000612	SCV001194219	likely pathogenic	Phenylketonuria	2019-11-12	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.782G>A(R261Q) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R261Q variant can be associated with classic or variant PKU. Sources cited for classification include the following: PMID 12409276, 23792259, 2574153, 8889590, 19394257, 22513348, 17935162, 12655546, 15557004 and 10479481. Classification of NM_000277.1(PAH):c.782G>A(R261Q) is based on the following criteria: This variant 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	RCV000078530	SCV001249180	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000000612	SCV001251468	pathogenic	Phenylketonuria		criteria provided, single submitter	research	The PAH c.782G>A (p.R261Q) missense variant has been reported in the compound heterozygous or homozygous state in individuals with phenylketonuria (PMID: 2574153; 17935162; 16765994)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000000612	SCV001448773	pathogenic	Phenylketonuria	2017-10-04	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000078530	SCV001755370	pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000000612	SCV001761116	pathogenic	Phenylketonuria	2020-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000612	SCV002016475	pathogenic	Phenylketonuria	2023-06-21	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000000612	SCV002059132	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: VCV000000582, PMID:2574153, PS1_S). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 25596310, 17935162) (PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25596310, 2014036, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.985, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000216, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102832, PMID:7556322,26666653, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	RCV000000612	SCV004035233	uncertain significance	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing	uncertain (or unknown) significance
Baylor Genetics	RCV000000612	SCV004201331	pathogenic	Phenylketonuria	2024-03-28	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000612	SCV005051901	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Neuberg Centre For Genomic Medicine, NCGM	RCV000000612	SCV005061253	pathogenic	Phenylketonuria	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.782G>A (p.Arg261Gln) variant in PAH gene has been reported previously in compound heterozygous state in multiple individuals affected with phenylketonuria (Jeannesson-Thivisol et al. 2015; Wang et al., 2007;). Experimental studies show this variant produced very low levels of PAH activity (Danecka et al. 2015; Jeannesson-Thivisol et al. 2015). The p.Arg261Gln variant is present with an allele frequency of 0.02% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on PAH gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 261 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The observed variant in PAH gene is absent in spouse.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000612	SCV005398976	pathogenic	Phenylketonuria	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar and has been observed as homozygous or compound heterozygous in individuals with classical PKU, and also in some individuals with mild PKU (PMID: 26666653). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000078530	SCV005414112	pathogenic	not provided	2024-02-13	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM3_very_strong, PS3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000612	SCV005418465	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PP3_Strong+PM3_VeryStrong
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000000612	SCV005438118	pathogenic	Phenylketonuria	2024-12-17	criteria provided, single submitter	clinical testing
OMIM	RCV000000612	SCV000020762	pathogenic	Phenylketonuria	2007-08-15	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078530	SCV000119697	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000000612	SCV000324888	not provided	Phenylketonuria		no assertion provided	literature only
Natera, Inc.	RCV000000612	SCV001453105	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078530	SCV001739558	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078530	SCV001931825	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078530	SCV001956078	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078530	SCV001975970	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904790	SCV004724094	pathogenic	PAH-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The PAH c.782G>A variant is predicted to result in the amino acid substitution p.Arg261Gln. This variant has been documented in numerous studies to be causative for phenylalanine hydroxylase deficiency (e.g., Bénit et al. 1999. PubMed ID: 10479481; Shi et al. 2012. PubMed ID: 21953985; Couce et al. 2013. PubMed ID: 23500595). In functional studies, the p.Arg261Gln substitution has been reported to reduce PAH enzyme activity to ~10-40% of control (e.g., Zurflüh et al. 2008. PubMed ID: 17935162; Danecka et al. 2015. PubMed ID: 25596310). The p.Arg261Gln substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and multiple other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/582/). Based on these observations, we also classify the c.782G>A (p.Arg261Gln) variant as pathogenic.