Submissions for variant NM_206933.4(USH2A):c.12343C>T (p.Arg4115Cys)

gnomAD frequency: 0.00056  dbSNP: rs111033275

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041719	SCV000065415	likely benign	not specified	2015-04-24	criteria provided, single submitter	clinical testing	p.Arg4115Cys in exon 63 of USH2A: This variant has been reported in 8 individual s with Usher syndrome and 2 individuals with retinitis pigmentosa. However, 3 of the individuals with Usher syndrome carried another pathogenic variant on the s ame allele and 4 of the 10 individuals carried 2 pathogenic variants in USH2A th at were sufficient to explain their disease. As a result, this variant is not ex pected to have clinical significance. It has also been identified in 32/66436 Eu ropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs111033275).
Eurofins Ntd Llc (ga)	RCV000727295	SCV000707355	uncertain significance	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000986518	SCV001135533	benign	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727295	SCV001220653	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074716	SCV001240309	uncertain significance	Retinal dystrophy	2019-04-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000727295	SCV002569694	uncertain significance	not provided	2022-06-29	criteria provided, single submitter	clinical testing	Identified in patients with Usher syndrome or retinitis pigmentosa in published literature, although additional clinical information and familial segregation information were not provided in some cases (Garcia-Garcia et al., 2011; Pierrache et al., 2016; van Huet et al., 2015); 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: 30245029, 25999674, 15015129, 26927203, 22334370, 18273898, 16963483, 27460420, 22004887, 17405132, 32483926)
Revvity Omics, Revvity	RCV000727295	SCV003828079	uncertain significance	not provided	2021-10-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041719	SCV004039210	likely benign	not specified	2023-08-23	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12343C>T (p.Arg4115Cys) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 250496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00031 vs 0.011), allowing no conclusion about variant significance. c.12343C>T has been reported in the literature in individuals affected with Usher Syndrome and Retinitis Pigmentosa (e.g. Pierrache_2016, Garcia-Garcia_2011, Reurink_2023, vanHuet_2015, Azaiez_2018) without evidence for causality. Additionally, co-occurrences with other pathogenic variants have been reported in cis with this variant (USH2A c.13274C>T, p.T4425M; USH2A c.13274C>T, p.T4425M; USH2A c.1876C>T, p.R626Ter) (e.g. vanWijk_2004, Bonnet_2016, Dreyer_2008) , providing supporting evidence for a benign role. 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: 30245029, 27460420, 18273898, 22004887, 26927203, 25999674, 15015129, 30902645). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=3) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004732592	SCV005361535	uncertain significance	USH2A-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The USH2A c.12343C>T variant is predicted to result in the amino acid substitution p.Arg4115Cys. This variant was reported in individuals with Usher syndrome 2 (van Wijk et al. 2004. PubMed ID: 15015129; Neveling et al. 2012. PubMed ID: 22334370; Table S12 Diñeiro et al. 2020. PubMed ID: 32483926). However, this variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD, which is likely too frequent to be a primary cause of disease. Though we suspect this variant may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.