Submissions for variant NM_032119.4(ADGRV1):c.8585A>G (p.Tyr2862Cys)

gnomAD frequency: 0.00014  dbSNP: rs876657827

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219980	SCV000271822	uncertain significance	not specified	2016-02-21	criteria provided, single submitter	clinical testing	The p.Tyr2862Cys variant in GPR98 has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Tyr2862Cys variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Tyr2862Cys variant is unc ertain.
Invitae	RCV001235514	SCV001408203	likely benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219980	SCV004029745	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.8585A>G (p.Tyr2862Cys) results in a non-conservative amino acid change located in the Na-Ca exchanger/integrin-beta4 domain (IPR003644) 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 1.6e-05 in 246580 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8585A>G has been reported in the literature as a non-informative genotype (second allele not specified or classified as a benign variant) in individuals affected with hearing loss (example, Garcia-Garcia_2013, Sloan-Heggen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23441107, 26969326, 35813073). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.