ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.10561T>C (p.Trp3521Arg) (rs111033264)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824783 SCV000065369 pathogenic Rare genetic deafness 2015-03-03 criteria provided, single submitter clinical testing The p.Trp3521Arg variant in USH2A has been reported in at least 10 individuals w ith Usher syndrome (Dreyer 2008, McGee 2010, Le Quesne Stabej 2012, Glockle 2014 ). At least 4 of these individuals were reported to carry another pathogenic USH 2A variant in trans (Le Quesne Stabej 2012). This variant has also been identifi ed by our laboratory in 3 Caucasian individuals with Usher syndrome, all of whom carried a second, loss-of-function variant in the USH2A gene. The Exome Aggrega tion Consortium (ExAC, has identified this varia nt in 2/66552 European chromosomes (dbSNP rs111033264). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency. Computational prediction tools and conse rvation analysis suggest that the variant may impact the protein. In summary, th e p.Trp3521Arg variant meets our criteria to be classified as pathogenic for Ush er syndrome in an autosomal recessive manner ( nalizedmedicince/LMM).
Broad Institute Rare Disease Group, Broad Institute RCV000041673 SCV000693910 pathogenic Usher syndrome, type 2A 2017-06-25 criteria provided, single submitter research
Counsyl RCV000665210 SCV000789287 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV001056065 SCV001220484 pathogenic not provided 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 3521 of the USH2A protein (p.Trp3521Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs111033264, ExAC 0.003%). This variant has been observed to be homozygous or in combination with another USH2A variant in individual(s) with retinitis pigmentosa (RP) or Usher syndrome (PMID: 24265693, 26969326), and also segregated with RP in a family (PMID: 28559085). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48352). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074824 SCV001240424 pathogenic Retinal dystrophy 2019-07-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001056065 SCV001246251 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376413 SCV001573541 likely pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.10561T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic.
GeneDx RCV001056065 SCV001772793 pathogenic not provided 2021-01-04 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 32581362, 27460420, 28559085, 30718709, 27318125, 22135276, 23591405, 18273898, 24265693, 20507924, 26969326, 28041643)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001056065 SCV001905659 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504880 SCV000598764 likely pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504880 SCV000926711 pathogenic Usher syndrome 2018-04-01 no assertion criteria provided research
Natera, Inc. RCV000041673 SCV001457063 pathogenic Usher syndrome, type 2A 2020-09-16 no assertion criteria provided clinical testing

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