Submissions for variant NM_206933.4(USH2A):c.6670G>T (p.Gly2224Cys)

gnomAD frequency: 0.00089  dbSNP: rs149553844

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191140	SCV000245549	uncertain significance	Retinitis pigmentosa 39	2013-04-10	criteria provided, single submitter	clinical testing	This variant was found once in our laboratory with a pathogenic variant [E767fs] and another missense variant [E3448K; phase undetermined] in a 32-year-old female with retinitis pigmentosa. Variant possibly pathogenic in recessive state; heterozygotes would be carriers.
Eurofins Ntd Llc (ga)	RCV000359124	SCV000339980	uncertain significance	not provided	2016-04-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765068	SCV000896268	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000359124	SCV001217863	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2224 of the USH2A protein (p.Gly2224Cys). This variant is present in population databases (rs149553844, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with USH2A-related retinopathy (PMID: 25412400, 27160483, 28041643). ClinVar contains an entry for this variant (Variation ID: 209202). 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. 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.
Blueprint Genetics	RCV001073314	SCV001238852	uncertain significance	Retinal dystrophy	2018-11-09	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000191140	SCV001573466	uncertain significance	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.6670G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV000359124	SCV001785928	likely pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25412400, 26633545, 32037395, 28041643, 36785559, 32531858, 35266249, 36819107, 34906470, 37734845, 38219857, 27160483, 36909829)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155115	SCV003845083	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.6670G>T (p.Gly2224Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00045 vs 0.011), allowing no conclusion about variant significance. c.6670G>T has been reported in the literature in individuals affected with inherited retinal disease, without strong evidence for causality (Khan_2016, Carss_2017, Jiman_2020, etc). These reports 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters classified the variant as VUS while two classified as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000504652	SCV004030344	uncertain significance	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV004530089	SCV004105190	uncertain significance	USH2A-related disorder	2023-04-11	criteria provided, single submitter	clinical testing	The USH2A c.6670G>T variant is predicted to result in the amino acid substitution p.Gly2224Cys. This variant was previously reported in the heterozygous state in at least three patients with autosomal recessive retinitis pigmentosa (Table S7, Consugar et al. 2015. PubMed ID: 25412400; Table S2, Carss et al. 2016. PubMed ID: 28041643; Khan et al. 2017. PubMed ID: 27160483; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). In all of these patients a second missense variant (p.Glu3448Lys) was also present, while in two of the patients a third truncating variant was also present. In one additional patient with RP this variant was in reported in a patient along with a truncating variant in the absence of the p.Glu3448Lys variant (Table S1, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216166497-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073314	SCV005071109	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504652	SCV000598823	likely pathogenic	Retinitis pigmentosa	2015-01-01	flagged submission	research
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002722	SCV001156415	pathogenic	Usher syndrome type 2A	2019-02-01	flagged submission	clinical testing
Natera, Inc.	RCV001002722	SCV001458132	uncertain significance	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000359124	SCV001954939	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000359124	SCV001969114	uncertain significance	not provided		no assertion criteria provided	clinical testing