Submissions for variant NM_206933.4(USH2A):c.802G>A (p.Gly268Arg)

gnomAD frequency: 0.00004  dbSNP: rs111033280

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041918	SCV000065614	pathogenic	Usher syndrome	2019-02-07	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Counsyl	RCV000675158	SCV000800775	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-06-29	criteria provided, single submitter	clinical testing
Invitae	RCV001060026	SCV001224686	pathogenic	not provided	2024-01-16	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 268 of the USH2A protein (p.Gly268Arg). This variant is present in population databases (rs111033280, gnomAD 0.005%). This missense change has been observed in individuals with Usher syndrome (PMID: 25356976, 29490346, 29625443). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48592). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074162	SCV001239732	pathogenic	Retinal dystrophy	2019-02-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001060026	SCV002319024	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27460420, 30245029, 32531858, 25356976, 20052763, 10729113, 26338283, 15325563, 28944237, 32319668, 31054281, 31456290, 33598457, 29625443, 32188678, 33124170, 32675063, 33090715, 32037395, 32749464, 27318125, 24944099, 18273898, 33535592, 22135276, 29490346, 35266249)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041918	SCV003928759	pathogenic	Usher syndrome	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.802G>A (p.Gly268Arg) results in a non-conservative amino acid change located in the LamG-like jellyroll fold domain (IPR006558) of the encoded protein sequence. Five 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 250826 control chromosomes. c.802G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Usher Syndrome (example, Stabej_2012, Bonnet_2016, Neuhaus_2017, Huang_2015, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. 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: 27460420, 25356976, 28944237, 15325563, 22135276, 32531858, 32637036). Seven 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV003450896	SCV004182949	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001826601	SCV004182950	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003450896	SCV004208255	pathogenic	Retinitis pigmentosa 39	2023-09-16	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001074162	SCV004708077	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003288	SCV001161371	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001826601	SCV002094014	pathogenic	Usher syndrome type 2A	2020-07-14	no assertion criteria provided	clinical testing