ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.752C>T (p.Pro251Leu) (rs746961144)

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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 RCV000223293 SCV000271569 uncertain significance not specified 2015-05-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Pro251Leu var iant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 1/9806 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). The proline (Pro) at position 251 is not evolutionarily conserved across species, with 2 mammals (dolphin and killer whale) and 10 fish species having a leucine (Leu) at this position. Addi tional computational prediction tools do not provide strong support for or again st an impact to the protein. This variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not sugg est an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Pr o251Leu variant is uncertain, the lack of evolutionarily conservation suggests t hat it is more likely to be benign.
Invitae RCV001212812 SCV001384409 uncertain significance not provided 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 251 of the CDH23 protein (p.Pro251Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs746961144, ExAC 0.01%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 228502). 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 leucine 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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