ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.8407G>A (p.Val2803Ile) (rs369697366)

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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 RCV000039284 SCV000062968 uncertain significance not specified 2013-12-10 criteria provided, single submitter clinical testing The Val2803Ile variant in CDH23 has now been identified by our laboratory in one individual with sloping sensorineural hearing loss and in one individual with a uditory neuropathy/dys-synchrony (ANSD). However, a second pathogenic variant in CDH23 was not found in any of these individuals and pathogenic variants in CDH2 3 have not been associated with ANSD, which suggest that this variant may not be related to these individuals' hearing loss. This variant has been identified in 0.02% (1/4260) of African American chromosomes by the NHLBI Exome sequencing pr oject (http://evs.gs.washington.edu/EVS/; dbSNP rs369697366); though this freque ncy is not high enough to rule out a pathogenic role. Computational analyses (bi ochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) d o not provide strong support for or against an impact to the protein. In summary , additional information is needed to determine the clinical significance of thi s variant.
Invitae RCV001243714 SCV001416889 uncertain significance not provided 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2803 of the CDH23 protein (p.Val2803Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs369697366, ExAC 0.08%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 46048). 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 C0". The isoleucine 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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