Submissions for variant NM_206933.4(USH2A):c.2522C>A (p.Ser841Tyr)

gnomAD frequency: 0.00569  dbSNP: rs111033282

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001775076	SCV000927009	benign	Usher syndrome	2020-12-24	reviewed by expert panel	curation	The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041813	SCV000065509	benign	not specified	2010-07-13	criteria provided, single submitter	clinical testing	This variant is not expected to have clinical significance due to an equal occur rence in probands and controls (Pennings 2004).
Eurofins Ntd Llc (ga)	RCV000041813	SCV000225951	benign	not specified	2014-12-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488324	SCV000574827	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000488324	SCV000605549	benign	not provided	2023-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000488324	SCV001033449	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000504801	SCV001257283	likely benign	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001100748	SCV001257284	likely benign	Usher syndrome type 2A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Athena Diagnostics	RCV000488324	SCV001477199	likely benign	not provided	2020-07-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000488324	SCV001864456	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32581362, 32707200, 30872814, 30245029, 28944237, 28653555, 28041643, 25773295, 19683999, 22004887, 25262649)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041813	SCV002512005	benign	not specified	2022-04-04	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.2522C>A (p.Ser841Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 250428 control chromosomes, including 9 homozygotes. This frequency is not higher than the estimated maximum expected (MPAF) for a pathogenic variant in USH2A causing Usher Syndrome (0.011), however the presence of homozygotes suggests a benign role for the variant. In addition, the variant is reported in certain subpopulations with even higher frequencies, e.g. in the Finnish (0.016) and Swedish (0.015), which are above the MPAF, indicating that the variant is benign. Although the variant, c.2522C>A, has been reported to be found in individuals affected with Usher Syndrome related phenotypes (HGMD), the Deafness Variation Database (DVD), classified the variant as benign, based on ethnic-specific minor allele frequencies (Shearer_2014, Azaiez_2018). To our knowledge no experimental evidence demonstrating the variant impact on protein function have been reported. 12 submitters, including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=1), VUS (n=4), likely benign (n=2) / benign (n=5; including the expert panel). Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV000488324	SCV005280611	benign	not provided		criteria provided, single submitter	not provided
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000041813	SCV000258289	uncertain significance	not specified	2015-02-05	flagged submission	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504801	SCV000598801	likely pathogenic	Retinitis pigmentosa	2015-01-01	flagged submission	research
Center for Statistical Genetics, Columbia University	RCV000754555	SCV000853293	uncertain significance	Hearing impairment	2018-10-08	flagged submission	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787896	SCV000926914	uncertain significance	Progressive cone dystrophy (without rod involvement)	2018-04-01	flagged submission	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000754555	SCV001439133	uncertain significance	Hearing impairment		flagged submission	research
Natera, Inc.	RCV001100748	SCV001459767	benign	Usher syndrome type 2A	2019-12-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000488324	SCV001925581	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000041813	SCV001958958	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000041813	SCV001971845	benign	not specified		no assertion criteria provided	clinical testing