Submissions for variant NM_022124.6(CDH23):c.1963G>A (p.Val655Ile)

gnomAD frequency: 0.00009  dbSNP: rs374805957

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724533	SCV000226835	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297753	SCV000363621	uncertain significance	CDH23-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000371125	SCV000363622	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	RCV000276507	SCV000363623	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000175362	SCV000710984	uncertain significance	not specified	2017-05-25	criteria provided, single submitter	clinical testing	The p.Val655Ile variant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 0.04% (15/34340) of Latino chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs374805957. Although this variant has been seen in the general popula tion, its frequency is not high enough to rule out a pathogenic role. This varia nt has been reported in ClinVar (Variation ID: 194888). Computational prediction tools and conservation analyses suggest that this variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val655Ile variant is uncertain.
Invitae	RCV000724533	SCV003299274	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 655 of the CDH23 protein (p.Val655Ile). This variant is present in population databases (rs374805957, gnomAD 0.04%). 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: 194888). 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: "Not Available"; Align-GVGD: "Class C25"). 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.
Ambry Genetics	RCV002517685	SCV003701632	uncertain significance	Inborn genetic diseases	2021-08-17	criteria provided, single submitter	clinical testing	The c.1963G>A (p.V655I) alteration is located in exon 18 (coding exon 17) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 1963, causing the valine (V) at amino acid position 655 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000724533	SCV003831496	uncertain significance	not provided	2019-02-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000724533	SCV004031652	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV001275933	SCV001461613	uncertain significance	Usher syndrome type 1	2020-04-15	no assertion criteria provided	clinical testing