Submissions for variant NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter)

gnomAD frequency: 0.00012  dbSNP: rs111033364

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824781	SCV000065401	pathogenic	Usher syndrome; Rare genetic deafness	2017-10-03	criteria provided, single submitter	clinical testing	The p.Trp3955X variant in USH2A has been reported in many probands with Usher sy ndrome, many of whom were homozygous or compound heterozygous (van Wijk 2004, Cr emers 2007, Jacobson 2008, Dreyer 2008, Jaijo 2009, LMM data). This variant has also been identified in 0.025% (32/128914) of European chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is not high enough to ru le out a pathogenic role. This nonsense variant leads to a premature termination codon at position 3955, which is predicted to lead to a truncated or absent pro tein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3_Very S trong, PP4.
Eurofins Ntd Llc (ga)	RCV000414231	SCV000344373	pathogenic	not provided	2016-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000414231	SCV000490872	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25262649, 19683999, 28944237, 29293505, 31817543, 25575603, 22135276, 18273898, 18463160, 26927203, 28749477, 29551606, 28945494, 29986705, 28984810, 28559085, 31370859, 15015129, 16963483, 31054281, 31266775, 31456290, 32581362, 32188678, 34426522, 33089500, 31589614, 33576794, 33105617, 33737949, 32037395)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414867	SCV000492761	pathogenic	Hearing impairment	2014-07-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000002451	SCV001162877	pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002451	SCV001194132	pathogenic	Usher syndrome type 2A	2019-12-26	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.11864G>A(W3955*) is classified as pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 27460420. Classification of NM_206933.2(USH2A):c.11864G>A(W3955*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000414231	SCV001213203	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp3955*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs111033364, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 22135276, 25575603, 29293505). ClinVar contains an entry for this variant (Variation ID: 2357). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074873	SCV001240477	pathogenic	Retinal dystrophy	2019-08-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000414231	SCV001246247	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PVS1, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000002451	SCV001366417	pathogenic	Usher syndrome type 2A	2019-10-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414231	SCV001446857	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000412373	SCV001573517	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.11864G>A 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: PVS1, PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000504922	SCV001950398	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Trp3955Ter variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Institute of Human Genetics, University Hospital Muenster	RCV001806999	SCV002054109	pathogenic	Rod-cone dystrophy	2021-05-11	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PM3,PP3,PP5
DASA	RCV001813732	SCV002061201	pathogenic	USH2A-Related Disorders	2022-01-05	criteria provided, single submitter	clinical testing	The c.11864G>A;p.(Trp3955*) variant creates a premature translational stop signal in the USH2A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:2357; PMID: 29293505; 27460420; 26927203; 25649381; 25575603; 25333064; 22135276; 21569298; 20507924) - PS4. The variant is present at low allele frequencies population databases (rs111033364 – gnomAD 0.01249%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Trp3955*) was detected in trans with a pathogenic variant (PMID: 29293505; 27460420; 25649381; 25575603; 25333064; 22135276; 21569298) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25575603) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000002451	SCV002556531	pathogenic	Usher syndrome type 2A	2022-03-11	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000002451	SCV002577544	pathogenic	Usher syndrome type 2A	2022-01-13	criteria provided, single submitter	clinical testing	PVS1, PM2, PP3, PP5
MGZ Medical Genetics Center	RCV000002451	SCV002581855	pathogenic	Usher syndrome type 2A	2022-09-05	criteria provided, single submitter	clinical testing
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000002451	SCV002756439	pathogenic	Usher syndrome type 2A	2022-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476913	SCV002787205	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114173	SCV003801311	pathogenic	Usher syndrome	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.11864G>A (p.Trp3955X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.2e-05 in 251168 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (9.2e-05 vs 0.011), allowing no conclusion about variant significance. c.11864G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Usher Syndrome (example, PMID: 27460420, 28944237). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV003314546	SCV004014696	pathogenic	Usher syndrome type 3A	2023-01-13	criteria provided, single submitter	clinical testing	The USH2A c.11864G>A (p.Trp3955Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The c.11864G>A variant is a founder variant in central European and is particularly common in the Slovenian population, where it has been estimated to account for over 80% disease-causing alleles among individuals with Usher syndrome type 2 (PMID: 27460420; PMID: 31817543). Across a selection of the available literature, the c.11864G>A variant is most commonly reported in association with Usher syndrome type 2, but has also been reported in individuals with non-syndromic retinitis pigmentosa (PMID: 15015129; PMID: 2564938; PMID: 27460420; PMID: 31817543). The highest frequency of this allele in the Genome Aggregation Database is 0.000279 in the European (non-Finnish) population, which includes one homozygote (version 3.1.2). Based on the available evidence, the c.11864G>A (p.Trp3955Ter) variant is classified as pathogenic for Usher syndrome type 2.
Genome-Nilou Lab	RCV000412373	SCV004182063	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002451	SCV004182064	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412373	SCV004207697	pathogenic	Retinitis pigmentosa 39	2023-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904796	SCV004718566	pathogenic	USH2A-related condition	2023-11-09	criteria provided, single submitter	clinical testing	The USH2A c.11864G>A variant is predicted to result in premature protein termination (p.Trp3955*). This variant has been reported many times in individuals with Usher syndrome and is noted to be one of the most common pathogenic variants in USH2A, being detected in ~22% of a cohort of patients (see for examples Bonnet et al. 2016. PubMed ID: 27460420; Lenarduzzi et al. 2015. PubMed ID: 25575603; Table S4 in Stone et al. 2017. PubMed ID: 28559085). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215901574-C-T). Nonsense variants in USH2A are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.
OMIM	RCV000002451	SCV000022609	pathogenic	Usher syndrome type 2A	2004-04-01	no assertion criteria provided	literature only
Counsyl	RCV000412373	SCV000487752	pathogenic	Retinitis pigmentosa 39	2016-10-27	no assertion criteria provided	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415089	SCV000492673	pathogenic	Congenital sensorineural hearing impairment	2016-02-12	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504922	SCV000598770	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504922	SCV000926715	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003260	SCV001161342	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV000002451	SCV001451982	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414231	SCV001956064	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414231	SCV001974079	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000002451	SCV004099463	pathogenic	Usher syndrome type 2A	2023-10-30	no assertion criteria provided	clinical testing