ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.2789C>T (p.Pro930Leu)

gnomAD frequency: 0.00003  dbSNP: rs763602387
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001068830 SCV001233963 uncertain significance not provided 2022-06-03 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 930 of the CDH23 protein (p.Pro930Leu). This variant is present in population databases (rs763602387, gnomAD 0.05%). 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: 862160). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. RCV001272546 SCV001454638 uncertain significance Usher syndrome type 1 2020-03-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001068830 SCV001549127 uncertain significance not provided no assertion criteria provided clinical testing The CDH23 p.Pro930Leu variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs763602387) and in control databases in 19 of 278972 chromosomes at a frequency of 0.00006811 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 14 of 30592 chromosomes (freq: 0.000458), East Asian in 2 of 19470 chromosomes (freq: 0.000103) and European (non-Finnish) in 3 of 127076 chromosomes (freq: 0.000024), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or Other populations. The p.Pro930 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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