Submissions for variant NM_206933.4(USH2A):c.7685T>C (p.Val2562Ala)

gnomAD frequency: 0.00586  dbSNP: rs56385601

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041915	SCV000065611	benign	not specified	2011-01-17	criteria provided, single submitter	clinical testing	Val2562Ala in exon 41 of USH2A: This variant has been reported in nine individua ls with a clinical diagnosis of Usher Syndrome types 1, 2 or 3 (Dreyer 2008, Jai jo 2009). However, several of these individuals already had other explanations f or their Usher syndrome (Jaijo 2009). In addition, this amino acid is not highly conserved acroos evolution, with the mouse and rat having an alanine at positio n 2562. In addition, this variant is listed in dbSNP (rs56385601 - no frequency data available) and has been identified in 6/278 (2.2%) probands tested by our l aboratory, none of whom had a variant on their second USH2A allele. In summary, this variant meets our criteria to be classified as benign.
Eurofins Ntd Llc (ga)	RCV000041915	SCV000230559	benign	not specified	2015-02-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000953014	SCV001099558	benign	not provided	2025-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000041915	SCV001477202	benign	not specified	2019-09-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000953014	SCV001839159	benign	not provided	2019-01-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31266775, 19683999, 23484092, 18273898, 20052763, 22681893, 26927203, 22004887)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041915	SCV002074296	benign	not specified	2022-01-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.7685T>C (p.Val2562Ala) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 251140 control chromosomes, predominantly at a frequency of 0.0095 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. This frequency is close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0065 vs 0.011), supporting a neutral outcome. Although reported frequently in the literature, to our knowledge, no occurrence of c.7685T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one report listed this variant along with two other pathogenic alleles in an individual with Usher syndrome, supporting a benign outcome (example, Hagag_2020). Five 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 benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000953014	SCV002821456	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS2
Genome-Nilou Lab	RCV003450893	SCV004183209	likely benign	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001271977	SCV004183210	likely benign	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000953014	SCV005280564	benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001271977	SCV001453604	benign	Usher syndrome type 2A	2019-12-23	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000953014	SCV001951787	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000953014	SCV001971374	likely benign	not provided		no assertion criteria provided	clinical testing