ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.623C>T (p.Thr208Ile)

gnomAD frequency: 0.00004  dbSNP: rs749123528
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Total submissions: 4
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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 RCV000825298 SCV000966593 uncertain significance not specified 2018-10-09 criteria provided, single submitter clinical testing The p.Thr208Ile variant in CDH23 has not been previously reported in individuals with hearing loss or Usher syndrome, but has been reported in 0.03% (11/33536) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. This variant is located in the last three ba ses of the exon, which is part of the 5? splice region. Computational tools do n ot predict altered splicing, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr208Il e variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
GeneDx RCV001766760 SCV001999354 uncertain significance not provided 2023-05-31 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001766760 SCV002135782 uncertain significance not provided 2022-07-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 208 of the CDH23 protein (p.Thr208Ile). This variant is present in population databases (rs749123528, gnomAD 0.03%). 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: 666805). 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 C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. RCV001830832 SCV002086834 uncertain significance Usher syndrome type 1 2020-07-29 no assertion criteria provided clinical testing

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