ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6664C>T (p.Arg2222Cys) (rs761082272)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000602312 SCV000712073 uncertain significance not specified 2016-05-02 criteria provided, single submitter clinical testing The p.Arg2222Cys variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 5/63898 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs761082272). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Th e arginine (Arg) at position 2222 is not highly conserved in mammals and evoluti onary distant species, and one mammal (Chinese hamster) carries a cysteine (Cys) at this position, raising the possibility that this change at this position may be tolerated. Additional computational prediction tools do not provide strong s upport for or against an impact to the protein. In summary, the clinical signif icance of this variant is uncertain.
Invitae RCV001241141 SCV001414136 uncertain significance not provided 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2222 of the CDH23 protein (p.Arg2222Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs761082272, ExAC 0.008%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 505005). 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 C15"). 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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