Submissions for variant NM_206933.4(USH2A):c.3405G>C (p.Arg1135Ser)

gnomAD frequency: 0.00001  dbSNP: rs372843685

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041827	SCV000065523	uncertain significance	not specified	2015-06-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg1135Ser va riant in USH2A has been identified by our laboratory in 1 individual with Usher syndrome who carried a pathogenic variant in another gene that was sufficient to explain their disease. It has also been identified in 2/66710 European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs372843685). Although this variant has been seen in the general population , its frequency is not high enough to rule out a pathogenic role. Arginine (Arg) at position 1135 is not conserved in mammals or evolutionarily distant species, and 2 species (X. tropicalis and zebrafish) carry a serine (Ser), raising the p ossibility that a change at this position may be tolerated. Additional computati onal prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg1135Ser var iant is uncertain, its lack of conservation suggests that it is more likely to b e benign.
Invitae	RCV001061173	SCV001225906	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1135 of the USH2A protein (p.Arg1135Ser). This variant is present in population databases (rs372843685, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48501). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Genome-Nilou Lab	RCV003450840	SCV004182344	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001831703	SCV004182345	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831703	SCV002093933	uncertain significance	Usher syndrome type 2A	2019-11-11	no assertion criteria provided	clinical testing