ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs746961144
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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 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001212812 SCV001384409 uncertain significance not provided 2022-03-03 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 251 of the CDH23 protein (p.Pro251Leu). This variant is present in population databases (rs746961144, gnomAD 0.008%). 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: 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, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics RCV002478766 SCV002779429 uncertain significance Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2021-07-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV001835729 SCV002087847 uncertain significance Usher syndrome type 1 2019-10-28 no assertion criteria provided clinical testing

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