ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.7552G>A (p.Val2518Met) (rs376617494)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150319 SCV000197407 uncertain significance not specified 2014-05-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Val2518Met vari ant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 0.01% (1/8388) of European American chromosomes by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs376 617494). Although this variant has been seen in the general population, its freq uency is not high enough to rule out a pathogenic role. The valine (Val) residue at position 2518 is highly conserved in mammals and evolutionary distant specie s, but several turtle species carry a methionine (Met) at this position, raising the possibility that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the Val2518 Met variant is uncertain, the conservation data suggest that is more likely to b e benign.
Illumina Clinical Services Laboratory,Illumina RCV000368231 SCV000363871 uncertain significance CDH23-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000275931 SCV000363872 uncertain significance Deafness, autosomal recessive 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.
Illumina Clinical Services Laboratory,Illumina RCV000314616 SCV000363873 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.
GeneDx RCV000658566 SCV000618170 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing The V2518M variant in the CDH23 gene has been reported previously, using alternate nomenclature of V278M, along with a second CDH23 variant in a child with autosomal recessive non-syndromic congenital hearing loss (Sloan-Heggen et al., 2016). This variant is observed in 5/66,704 alleles (0.0075%) from individuals of non-Finnish European background, and 1/9,800 alleles (0.01%) from individuals of African background, in the ExAC dataset (Lek et al., 2016). The V2518M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V2518M as a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658566 SCV000780342 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing

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