ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.1515-12G>A (rs369396703)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089674 SCV001245157 uncertain significance Usher syndrome 2019-11-26 reviewed by expert panel curation The allele frequency of the c.1515-12G>A variant in the CDH23 gene is 0.01% (1/9692) of Ashkenazi Jewish chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the c.1515-12G>A variant may impact splicing (PP3). This variant was reported in two patients with Usher syndrome (GeneDx unpublished data SCV000564845.2, Human Genetics Radboudumc unpublished data SCV000804605.2) and one with sloping sensorineural hearing loss (LMM unpublished data SCV000271550.2). The probands with Usher syndrome had a suspected-pathogenic variant in CDH23 with an unknown phase (PM3; SCV000564845.2, SCV000804605.2). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2_Supporting, PM3, PP3).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000216452 SCV000271550 uncertain significance not specified 2015-08-11 criteria provided, single submitter clinical testing The c.1515-12G>A variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/26694 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti; rs369396703). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. This var iant is located in the 3' splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the c.1515-12G>A variant is uncertain.
GeneDx RCV000486086 SCV000564845 likely pathogenic not provided 2013-10-29 criteria provided, single submitter clinical testing The c.1515-12 G>A splice site variant in the CDH23 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. In silico algorithms predict that the c.1515-12G>A variant create an upstream cryptic splice acceptor site that is stronger than the wild-type splice acceptor site. One in silico algorithm also predicted that the wild-type splice acceptor site is destroyed. The c.1515-12 G>A variant was not observed at any significant frequency in approximately 6,200 individuals of European and African American ancestry in an external variant database. The c.1515-12 G>A variant in the CDH23 gene is a strong candidate for a pathogenic, although the possibility that it is a benign polymorphism cannot be completed excluded.
Human Genetics - Radboudumc,Radboudumc RCV000678531 SCV000804605 uncertain significance Usher syndrome type 1D 2016-09-01 no assertion criteria provided clinical testing

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