ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4664G>A (p.Arg1555His) (rs727502927)

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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 RCV000150295 SCV000197350 uncertain significance not specified 2013-07-09 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg1555His vari ant in CDH23 has not been reported in individuals with hearing loss and was not identified in large population studies. The arginine (Arg) residue at position 1 555 is not conserved across species, with dog having a histidine (His) at this p osition. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg1555His varia nt may not impact the protein. However, this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of this varia nt cannot be determined; however, based upon the conservation and computational data, we would lean towards a more likely benign role.
Invitae RCV001239186 SCV001412037 uncertain significance not provided 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1555 of the CDH23 protein (p.Arg1555His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs727502927, 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: 162912). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". 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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