Submissions for variant NM_206933.4(USH2A):c.12823T>A (p.Ser4275Thr)

gnomAD frequency: 0.00061  dbSNP: rs138607917

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215653	SCV000272889	uncertain significance	not specified	2015-05-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser4275Thr va riant in USH2A has previously been reported in one individual with Usher syndrom e and one individual with isolated retinitis pigmentosa; however, a variant affe cting the remaining copy of USH2A was not identified in either individual (Le Qu esne Stabej 2012, Wang 2014). This variant has been reported in 0.1% (48/66670) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs138607917); however, this frequency is not high enoug h to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ser4275Thr variant is unce rtain, the available frequency data suggests that it is more likely to be benign .
Eurofins Ntd Llc (ga)	RCV000726657	SCV000701989	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726657	SCV000884863	uncertain significance	not provided	2018-04-12	criteria provided, single submitter	clinical testing	The USH2A: p.Ser4275Thr variant (rs138607917) was reported in one individual from a cohort of patients with inherited eye disease subject to genetic testing (Haer-Wigman 2017). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.09 percent in the European non-Finnish population (identified on 119 out of 126,332 chromosomes) and has been reported to the ClinVar database (Variation ID: 229619). The serine at position 4275 is moderately conserved considering 12 species (Alamut v2.11) and computational analyses of the effects of the p.Ser4275Thr variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ser4275Thr variant with certainty.
Athena Diagnostics	RCV000726657	SCV001146600	uncertain significance	not provided	2018-12-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726657	SCV001413500	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000726657	SCV001820979	likely benign	not provided	2022-03-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in unrelated patients with retinitis pigmentosa in published literature (Wang et al., 2014; Costa et al., 2017; Haer-Wigman et al., 2017); however, clinical information was limited; This variant is associated with the following publications: (PMID: 28224992, 22135276, 28912962, 25097241)
Myriad Genetics, Inc.	RCV001272948	SCV002060144	uncertain significance	Usher syndrome type 2A	2021-11-09	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.12823T>A(S4275T) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. S4275T has been observed in cases with relevant disease (PMID: 28912962, 28224992, 25097241, 22135276). Functional assessments of this variant are not available in the literature. S4275T has been observed in population frequency databases (gnomAD: NFE 0.09%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.12823T>A(S4275T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215653	SCV002500314	uncertain significance	not specified	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12823T>A (p.Ser4275Thr) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251910 control chromosomes (gnomAD, Le Quesne Stabej_2012), predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00062 vs 0.011), allowing no conclusion about variant significance. c.12823T>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (Wang_2014, Haer-Wigman_2017, Costa_2017). 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. Eight ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000726657	SCV004125596	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	USH2A: BP4
Natera, Inc.	RCV001272948	SCV001455399	uncertain significance	Usher syndrome type 2A	2020-01-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732793	SCV005351855	uncertain significance	USH2A-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The USH2A c.12823T>A variant is predicted to result in the amino acid substitution p.Ser4275Thr. This variant has been reported with uncertain significance in cohort studies of retinal disease (Haer-Wigman et al. 2017. PubMed ID: 28224992; Table S1, Weisschuh et al. 2024. PubMed ID: 37734845). This variant is reported in 0.096% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.