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

gnomAD frequency: 0.00006  dbSNP: rs111033264

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org) 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 (http://pcpgmwww.partners.org/perso nalizedmedicince/LMM).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056065	SCV001220484	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 3521 of the USH2A protein (p.Trp3521Arg). This variant is present in population databases (rs111033264, gnomAD 0.006%). This missense change has been observed in individual(s) with retinitis pigmentosa (RP) or Usher syndrome (PMID: 24265693, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48352). 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 USH2A protein function with a positive predictive value of 80%. 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 Center for Human Genetics Tuebingen	RCV001056065	SCV001246251	pathogenic	not provided	2024-09-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PM2
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	2024-01-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 26969326, 20507924, 23591405, 27460420, 28041643, 30718709, 32531858, 24265693, 18273898, 22135276, 27318125, 28559085, 32581362, 36011334, 35266249, 32037395, 31964843, 36524988, 32313182, 34440443, 34662339, 25999674, 34906470, 36785559, 27957503, 32281467, 28944237)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001056065	SCV001905659	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504880	SCV002074353	pathogenic	Usher syndrome	2022-01-19	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.10561T>C (p.Trp3521Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251148 control chromosomes. c.10561T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Usher Syndrome (example, Eisenberger_2013, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287354	SCV002578083	pathogenic	See cases	2021-03-05	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM2,PP1,PP3,PP4,PP5
Fulgent Genetics, Fulgent Genetics	RCV000665210	SCV002810275	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001376413	SCV004182539	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000041673	SCV004182540	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376413	SCV004208160	pathogenic	Retinitis pigmentosa 39	2024-03-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074824	SCV005068922	likely pathogenic	Retinal dystrophy	2021-01-01	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
Department of Clinical Genetics, Copenhagen University Hospital, 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
PreventionGenetics, part of Exact Sciences	RCV004732588	SCV005355329	pathogenic	USH2A-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The USH2A c.10561T>C variant is predicted to result in the amino acid substitution p.Trp3521Arg. This variant has been reported in multiple individuals with Usher syndrome type IIa or non-syndromic retinitis pigmentosa (see for examples Dreyer et al. 2008. PubMed ID: 18273898; Eisenberger et al. 2013. PubMed ID: 24265693; McGee et al. 2010. PubMed ID: 20507924, Supplementary table 1, Weisschuh et al. 2024. PubMed ID: 37734845). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/48352). Given the evidence, we interpret c.10561T>C (p.Trp3521Arg) as pathogenic.