ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.1672G>A (p.Val558Met) (rs780661396)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001105171 SCV001262095 uncertain significance Deafness, autosomal recessive 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 2019-10-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 558 of the CDH23 protein (p.Val558Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs780661396, ExAC 0.04%). This variant has not been reported in the literature in individuals with CDH23-related disease. ClinVar contains an entry for this variant (Variation ID: 228485). 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: "Tolerated"; PolyPhen-2: "Not Available"; 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.

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