ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.782G>A (p.Arg261Gln) (rs5030849)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
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).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078530 SCV000110386 pathogenic not provided 2016-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000078530 SCV000239072 pathogenic not provided 2020-04-17 criteria provided, single submitter clinical testing Published functional studies on R261Q demonstrate a decrease in PAH activity (Okano et al., 1991; Danecka et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30275481, 30747360, 31028937, 31355225, 30963030, 8825928, 21527427, 8487271, 27121329, 30037505, 29499199, 19194782, 9323556, 23500595, 22975760, 28676969, 27264808, 25750018, 11999982, 27682710, 26759449, 26919687, 26655635, 26803807, 24296287, 2574153, 21953985, 2014036, 10479481, 19036622, 25596310, 24401910, 12655546, 23559577, 25087612, 17935162)
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
Invitae RCV000000612 SCV000629215 pathogenic Phenylketonuria 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 261 of the PAH protein (p.Arg261Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs5030849, ExAC 0.04%). This variant has been reported as homozygous or in combination with a different PAH variant in multiple individuals affected with PKU (PMID: 16765994, 2574153). ClinVar contains an entry for this variant (Variation ID: 582). Experimental studies have shown that this variant impairs protein function in vitro with the resulting enzyme retaining some residual activity (PMID: 10479481, 25596310, 17935162). 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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078530 SCV001249180 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
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
New York Genome Center RCV000000612 SCV001761116 pathogenic Phenylketonuria 2020-07-10 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 pathogenic Phenylketonuria 2016-10-20 no assertion criteria 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
Human Genetics - Radboudumc,Radboudumc RCV000078530 SCV001956078 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.