ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.2032G>A (p.Val678Ile)

gnomAD frequency: 0.00003  dbSNP: rs547668692
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Total submissions: 3
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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 RCV000216752 SCV000271553 uncertain significance not specified 2016-01-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val678Ile var iant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 12/65798 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs547668692). Computa tional prediction tools and conservation analyses suggest that the p.Val678Ile v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. Of note, the valine (Val) at position 678 is not conserved with 1 mammal (shrew) and 10 lower species (birds, amphibians, reptil es, fish) having an isoleucine (Ile) at this position, supporting that a change at this position may be tolerated. In summary, while the clinical significance o f the p.Val678Ile variant is uncertain, these data suggest that it is more likel y to be benign.
Invitae RCV001361168 SCV001557134 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 678 of the CDH23 protein (p.Val678Ile). This variant is present in population databases (rs547668692, gnomAD 0.02%). 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: 228487). 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.
Natera, Inc. RCV001833195 SCV002094440 uncertain significance Usher syndrome type 1 2019-10-28 no assertion criteria provided clinical testing

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