Submissions for variant NM_206933.4(USH2A):c.13832C>T (p.Ala4611Val)

gnomAD frequency: 0.00003  dbSNP: rs376077079

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001295873	SCV001484824	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4611 of the USH2A protein (p.Ala4611Val). This variant is present in population databases (rs376077079, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 19737284). ClinVar contains an entry for this variant (Variation ID: 999829). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C55". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV003323848	SCV004029986	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.13832C>T (p.Ala4611Val) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250830 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.13832C>T has been reported in the literature in an individual affected with Usher Syndrome in cis with a small in-frame deletion variant, and no variant detected in trans (Nakanishi_2009). 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 publication has been ascertained in the context of this evaluation (PMID: 19737284). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003449846	SCV004183122	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001830130	SCV004183123	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830130	SCV002088241	uncertain significance	Usher syndrome type 2A	2020-10-21	no assertion criteria provided	clinical testing