Submissions for variant NM_206933.4(USH2A):c.15496A>G (p.Ile5166Val)

gnomAD frequency: 0.00006  dbSNP: rs111033419

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041788	SCV000065484	uncertain significance	not specified	2009-05-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001276136	SCV002060157	uncertain significance	Usher syndrome type 2A	2021-11-09	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.15496A>G(I5166V) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. I5166V has been observed in cases with relevant disease (PMID: 27460420, 32531858, 26969326). Functional assessments of this variant are not available in the literature. I5166V has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.15496A>G(I5166V) 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	RCV000041788	SCV002599043	uncertain significance	not specified	2022-09-02	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.15496A>G (p.Ile5166Val) results in a conservative amino acid change in 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 4.2e-05 in 282882 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4.2e-05 vs 0.011), allowing no conclusion about variant significance. c.15496A>G has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (Sloan-Heggen_2016, Bonnet_2016, Weisschuh_2020, Fakin_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504925	SCV002814815	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513599	SCV003522993	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5166 of the USH2A protein (p.Ile5166Val). This variant is present in population databases (rs111033419, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 26969326, 27460420, 32531858). ClinVar contains an entry for this variant (Variation ID: 48465). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460550	SCV004208215	uncertain significance	Retinitis pigmentosa 39	2023-11-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276136	SCV001461988	uncertain significance	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing