Submissions for variant NM_022124.6(CDH23):c.1672G>A (p.Val558Met)

gnomAD frequency: 0.00011  dbSNP: rs780661396

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220115	SCV000271551	uncertain significance	not specified	2017-03-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val558Met var iant in CDH23 has been previously identified by our laboratory in one individual with hearing loss due to an alternate etiology. This variant has been identifie d in 8/35828 European and 4/10394 South Asian chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs780661396). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. The valine (Val) at position 558 is not conserved in mammals or evolutionarily distant species and 2 mammals (chimpanze e and elephant) carry a methionine (Met), supporting that this change may be tol erated. Additional computational prediction tools suggest that the p.Val558Met variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. In summary, while the clinical significance of t he p.Val558Met variant is uncertain, the conservation and computational data sug gest that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV001105170	SCV001262094	uncertain significance	Usher syndrome type 1D	2018-01-12	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	RCV001105171	SCV001262095	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-12	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	RCV001239936	SCV001412842	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 558 of the CDH23 protein (p.Val558Met). This variant is present in population databases (rs780661396, 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: 228485). 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.
Genome-Nilou Lab	RCV001105171	SCV001781426	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001105170	SCV001781427	uncertain significance	Usher syndrome type 1D	2021-07-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500707	SCV002814025	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-07-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517535	SCV003728698	uncertain significance	Inborn genetic diseases	2021-09-16	criteria provided, single submitter	clinical testing	The c.1672G>A (p.V558M) alteration is located in exon 16 (coding exon 15) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 1672, causing the valine (V) at amino acid position 558 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001275928	SCV001461608	uncertain significance	Usher syndrome type 1	2020-04-11	no assertion criteria provided	clinical testing