ClinVar Miner

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

gnomAD frequency: 0.00031  dbSNP: rs201942629
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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, Mass General Brigham 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 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2126 of the CDH23 protein (p.Arg2126His). This variant is present in population databases (rs201942629, gnomAD 0.05%). 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: 504556). 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.
GeneDx RCV001248681 SCV002013366 uncertain significance not provided 2023-03-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001275573 SCV001460822 uncertain significance Usher syndrome type 1 2020-04-17 no assertion criteria provided clinical testing

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