Submissions for variant NM_153676.4(USH1C):c.2191C>T (p.Arg731Trp)

gnomAD frequency: 0.00001  dbSNP: rs397517874

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041269	SCV000064960	uncertain significance	not specified	2012-03-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg731Trp varia nt in USH1C has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or a gainst an impact to the protein. In summary, the clinical significance of this v ariant cannot be determined with certainty.
Counsyl	RCV000669240	SCV000793972	uncertain significance	Usher syndrome type 1C; Autosomal recessive nonsyndromic hearing loss 18A	2017-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361788	SCV001557778	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 431 of the USH1C protein (p.Arg431Trp). This variant is present in population databases (rs397517874, gnomAD 0.05%). This missense change has been observed in individual(s) with deafness (PMID: 23967202). ClinVar contains an entry for this variant (Variation ID: 47993). 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: "Possibly Damaging"; 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.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375307	SCV001571929	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PP3_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041269	SCV004241483	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: USH1C c.1291C>T (p.Arg431Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250982 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in USH1C causing Usher Syndrome (5.6e-05 vs 0.0029), allowing no conclusion about variant significance. c.1291C>T has been reported in the literature in individuals affected with hearing loss and/or retinal degeneration without strong evidence of causality (Miyagawa_2013, Rodriguez-Muoz_2020, Bahena_2022). These reports do 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: 23967202, 32036094, 34148116). Four 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.
Natera, Inc.	RCV001272254	SCV001454058	uncertain significance	Usher syndrome type 1C	2020-09-16	no assertion criteria provided	clinical testing