Submissions for variant NM_206933.4(USH2A):c.8392G>A (p.Gly2798Arg)

gnomAD frequency: 0.00001  dbSNP: rs397518037

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041926	SCV000065622	uncertain significance	not specified	2016-09-15	criteria provided, single submitter	clinical testing	The p.Gly2798Arg variant in USH2A has not been reported in any individuals with hearing loss or Usher syndrome in any other families. This variant has been iden tified in 1/66738 chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs397518037); however, its frequency is not high enough to rule out a pathogenic role. The Glycine (Gly) at position 2798 is not highly conserved in mammals and evolutionary distant species, and several specie s including 2 mammals (prairie vole and black flying fox) carry a arginine (Arg) , raising the possibility that the change at this position may be tolerated. Add itional computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of the p.Gly2798Arg variant is uncer tain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001303130	SCV001492365	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2798 of the USH2A protein (p.Gly2798Arg). This variant is present in population databases (rs397518037, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48600). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV003450901	SCV004182810	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001831707	SCV004182811	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831707	SCV002090823	uncertain significance	Usher syndrome type 2A	2019-11-11	no assertion criteria provided	clinical testing