Submissions for variant NM_206933.4(USH2A):c.10451G>A (p.Arg3484Gln)

gnomAD frequency: 0.00006  dbSNP: rs771999994

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239748	SCV001412645	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3484 of the USH2A protein (p.Arg3484Gln). This variant is present in population databases (rs771999994, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 30073356). ClinVar contains an entry for this variant (Variation ID: 965326). 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 not 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479301	SCV004223502	uncertain significance	not specified	2023-11-01	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.10451G>A (p.Arg3484Gln) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250938 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (8.4e-05 vs 0.011), allowing no conclusion about variant significance. c.10451G>A has been reported in the literature in an individual affected with Usher Syndrome (e.g. Galli-Resta_2018). This report does 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. The following publications have been ascertained in the context of this evaluation (PMID: 29343940, 30073356). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394863	SCV006059173	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-11-22	criteria provided, single submitter	research
Natera, Inc.	RCV001828934	SCV002088357	uncertain significance	Usher syndrome type 2A	2020-01-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004733201	SCV005362983	uncertain significance	USH2A-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The USH2A c.10451G>A variant is predicted to result in the amino acid substitution p.Arg3484Gln. This variant has been reported with uncertain significance in an individual with Usher syndrome (Galli-Resta et al. 2018. PubMed ID: 30073356). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.