Submissions for variant NM_206933.4(USH2A):c.12445T>C (p.Trp4149Arg)

gnomAD frequency: 0.00956  dbSNP: rs115884084

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041721	SCV000065417	benign	not specified	2012-05-07	criteria provided, single submitter	clinical testing	Trp4149Arg in Exon 63 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 2.7% (100/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs115884084).
Eurofins Ntd Llc (ga)	RCV000041721	SCV000341026	benign	not specified	2016-04-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513931	SCV000610224	benign	not provided	2017-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000513931	SCV001092701	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000513931	SCV001835438	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27884173, 18723146, 22139616, 25262649)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041721	SCV002500136	benign	not specified	2022-03-05	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12445T>C (p.Trp4149Arg) results in a non-conservative amino acid change in 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 0.0023 in 250364 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in USH2A causing Usher Syndrome phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature, to our knowledge, no penetrant association of c.12445T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV003450761	SCV004181994	benign	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450760	SCV004181995	benign	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513931	SCV004562854	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000513931	SCV005287608	benign	not provided		criteria provided, single submitter	not provided