Submissions for variant NM_206933.4(USH2A):c.6883G>A (p.Gly2295Arg)

gnomAD frequency: 0.00002  dbSNP: rs768253909

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000416248	SCV000493415	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602087	SCV000713806	uncertain significance	not specified	2018-01-20	criteria provided, single submitter	clinical testing	The p.Gly2295Arg variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 16/111388 Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNPrs768253909). This variant has been reported in ClinVar (Var iation ID 374591). Computational prediction tools and conservation analysis sugg est that the p.Gly2295Arg variant may impact the protein and in silico splice pr ediction tools suggest that this variant may create a novel splice acceptor site . However, these tools are not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly2295Arg variant is uncertain. ACM G/AMP Criteria applied: PP3.
Invitae	RCV000416248	SCV001224653	uncertain significance	not provided	2022-08-05	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 2295 of the USH2A protein (p.Gly2295Arg). This variant is present in population databases (rs768253909, gnomAD 0.01%). 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: 374591). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Fulgent Genetics, Fulgent Genetics	RCV002488860	SCV002776270	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-31	criteria provided, single submitter	clinical testing
DBGen Ocular Genomics	RCV003389472	SCV004101751	likely pathogenic	Retinitis pigmentosa 39	2021-01-01	criteria provided, single submitter	clinical testing	Class 4 ACMG Guidelines, 2015
Natera, Inc.	RCV001271992	SCV001453620	uncertain significance	Usher syndrome type 2A	2020-01-17	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003330661	SCV004037516	not provided	USH2A-Related Disorders		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 08-21-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.