ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6377G>A (p.Arg2126His) (rs201942629)

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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 RCV000611377 SCV000710989 uncertain significance not specified 2016-06-02 criteria provided, single submitter clinical testing The p.Arg2126His variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 5/9762 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs148497691). Although this variant has been seen in the general p opulation, its frequency is not high enough to rule out a pathogenic role. The a rginine (Arg) at position 2126 is not highly conserved in mammals and evolutiona ry distant species, and 2 mammals (white rhinoceros and Chinese hamster) carry a histidine (His), raising the possibility that this change at this position may be tolerated. However, additional computational prediction tools suggest that th is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. In summary, the clinical significance of the p.A rg2126His variant is uncertain.
Invitae RCV001248681 SCV001422186 uncertain significance not provided 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2126 of the CDH23 protein (p.Arg2126His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201942629, ExAC 0.05%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 504556). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C25". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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