Submissions for variant NM_206933.4(USH2A):c.188G>A (p.Arg63Gln)

gnomAD frequency: 0.00011  dbSNP: rs369806765

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314425	SCV001504959	uncertain significance	not provided	2022-04-29	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 63 of the USH2A protein (p.Arg63Gln). This variant is present in population databases (rs369806765, gnomAD 0.04%). This missense change has been observed in individual(s) with deafness (PMID: 23767834). ClinVar contains an entry for this variant (Variation ID: 1015543). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV002282515	SCV002572312	uncertain significance	not specified	2022-08-24	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.188G>A (p.Arg63Gln) 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 4e-05 in 250918 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.188G>A has been reported in the literature as a non-informative genotype (second allele pathogenicity not certain) in at-least one individual affected with deafness (example: Yang_2013). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003449894	SCV004183004	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001835553	SCV004183005	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835553	SCV002094037	uncertain significance	Usher syndrome type 2A	2020-02-29	no assertion criteria provided	clinical testing