ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.1411G>A (p.Glu471Lys)

gnomAD frequency: 0.00001  dbSNP: rs778511495
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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 RCV000825885 SCV000967370 uncertain significance not specified 2018-04-11 criteria provided, single submitter clinical testing The p.Glu471Lys variant in CDH23 has been previously detected by our laboratory in one individual with sensorineural hearing loss who carried a second CDH23 var iant of uncertain significance; however the configuration of the variants (in ci s or in trans) was not determined. The variant was also identified in 5/246240 g eneral population chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs778511495). Although this variant has been s een in the general population, its frequency is not high enough to rule out a pa thogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu471Lys variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3.
GeneDx RCV001772149 SCV001992536 uncertain significance not provided 2019-02-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Invitae RCV001772149 SCV002177826 uncertain significance not provided 2022-05-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 471 of the CDH23 protein (p.Glu471Lys). This variant is present in population databases (rs778511495, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive deafness and/or Usher syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 667208). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C55"). 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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