ClinVar Miner

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

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Total submissions: 15
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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 2018-07-06 criteria provided, single submitter clinical testing The R261Q missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. Homozygosity for the R261Q variant has been reported in association with both benign hyperphenylalaninemia (HPA) and atypical PKU requiring dietary treatment. The offspring of mothers homozygous for R261Q have been reported with maternal PKU (Superti-Furga et al., 1991; Kleiman et al., 1993). However, patients compound heterozygous for R261Q and other variants, including severe variants, have been reported with both classic PKU and mild benign HPA indicating that the R261Q variant can be associated with a range of clinical phenotypes (Kleiman et al., 1993), including BH4 responsiveness. However, BH4 responsiveness was inconsistent in patients with R261Q (Zurfluh et al., 2008; Staudigl et al., 2011).
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 2020-01-03 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.
Integrated Genetics/Laboratory Corporation of America 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 2015-06-08 criteria provided, single submitter clinical testing
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 2019-10-01 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)
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

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