Submissions for variant NM_022124.6(CDH23):c.9928C>T (p.Arg3310Cys)

gnomAD frequency: 0.00018  dbSNP: rs200124827

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658120	SCV000779891	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing	The R3310C variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R3310C variant is observed in 56/269816 (0.0208%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). The R3310C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R3310C as a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001106301	SCV001263349	uncertain significance	Usher syndrome type 1D	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001106302	SCV001263350	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000658120	SCV001416167	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3310 of the CDH23 protein (p.Arg3310Cys). This variant is present in population databases (rs200124827, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 546270). 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 CDH23 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.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375333	SCV001572003	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Supporting, PP3_Supporting
Genome-Nilou Lab	RCV001106301	SCV001737279	uncertain significance	Usher syndrome type 1D	2021-06-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835062	SCV002086409	uncertain significance	Usher syndrome type 1	2019-10-28	no assertion criteria provided	clinical testing