Submissions for variant NM_206933.4(USH2A):c.6937G>T (p.Gly2313Cys)

gnomAD frequency: 0.00014  dbSNP: rs199840367

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432643	SCV000525066	likely pathogenic	not provided	2023-04-18	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: 34758253, 27032803, 26261414, 26306921, 34426522, 31589614, 31456290, 34335733, 28981474)
CeGaT Center for Human Genetics Tuebingen	RCV000432643	SCV000891881	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000432643	SCV001202175	pathogenic	not provided	2024-01-22	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 2313 of the USH2A protein (p.Gly2313Cys). This variant is present in population databases (rs199840367, gnomAD 0.02%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 26261414, 26306921, 27032803, 28981474; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 384319). 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	RCV001074794	SCV001240391	pathogenic	Retinal dystrophy	2019-07-03	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095706	SCV001251524	likely pathogenic	Retinitis pigmentosa 39		criteria provided, single submitter	research	The USH2A c.6937G>T (p.G2313C) variant has been reported in the compound heterozygous state in individuals with isolated RP (PMID: 26261414; 26306921; 27032803; 28981474).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271497	SCV002555737	pathogenic	Usher syndrome	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.6937G>T (p.Gly2313Cys) results in a non-conservative amino acid change located in the Fibronectin type III repeat domain (IPR003961) 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 0.00012 in 250934 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in USH2A causing Usher Syndrome (0.011), allowing no conclusion about variant significance. c.6937G>T has been reported in the literature in multiple individuals affected with retinitis pigmentosa (e.g. Sharon_2015, Bravo-Gil_2016, Comander_2017, Koyanagi_2019, Jauregui_2020, Karali_2022, Ganapathi_2022, Sen_2023). 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. Nine other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002272234	SCV002556442	uncertain significance	Cone-rod dystrophy 3	2021-04-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533027	SCV004113879	pathogenic	USH2A-related disorder	2022-11-10	criteria provided, single submitter	clinical testing	The USH2A c.6937G>T variant is predicted to result in the amino acid substitution p.Gly2313Cys. This variant has been reported in the compound heterozygous state in two siblings with autosomal recessive retinitis pigmentosa (arRP) (Bravo-Gil et al. 2016. PubMed ID: 27032803). It was also identified in the compound heterozygous state in another patient with arRP (Beryozkin et al. 2015. PubMed ID: 26306921, Table 1, MOL1234). Also, this variant was reported in another patient with non-syndromic retinitis pigmentosa. No other information was provided in this study (Sharon and Banin. 2015. PubMed ID: 26261414, Table 2). It was recently reported in the heterozygous state in a patient with pericentral RP. This patient was also heterozygous in USH2A for a known pathogenic nonsense variant and a second rare missense variant (Comander et al. 2017. PubMed ID: 28981474, Family #26 in Table 2). We have also observed the c.6937G>T variant along with a second pathogenic variant in two patients at PreventionGenetics. Taken together, we interpret this variant as pathogenic.
Baylor Genetics	RCV001095706	SCV004207723	likely pathogenic	Retinitis pigmentosa 39	2024-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000432643	SCV004238796	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001074794	SCV004707956	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992295	SCV004810330	likely pathogenic	Usher syndrome type 2A	2024-04-04	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003268	SCV001161351	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV001095706	SCV001760015	pathogenic	Retinitis pigmentosa 39		no assertion criteria provided	clinical testing