ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.3178C>T (p.Arg1060Trp) (rs201536811)

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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, Partners HealthCare Personalized Medicine RCV000217321 SCV000271556 uncertain significance not specified 2015-05-17 criteria provided, single submitter clinical testing The p.Arg1060Trp variant in CDH23 has been previously reported in 6 probands wit h Usher syndrome, one individual with possible Usher syndrome, and one individua l with sensorineural hearing loss (Astuto 2002, Roux 2006, Cremers 2007, Jaijo 2 010, Bonnet 2011, Kimberling 2010, Vozzi 2011, Bujakowska 2014). However, most o f these individuals did not carry a second variant in CDH23 and two of the Usher individuals had pathogenic variants identified in other Usher syndrome genes th at explain their clinical manifestations (Vozzi 2011, Bonnet 2011). This variant has been identified in 0.06% (40/66008) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201536811); however, this frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Arg1060Trp vari ant is uncertain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726009 SCV000341197 uncertain significance not provided 2018-06-20 criteria provided, single submitter clinical testing
GeneDx RCV000726009 SCV000568155 uncertain significance not provided 2016-05-19 criteria provided, single submitter clinical testing The R1060W variant in the CDH23 gene has been reported previously in association with Usher syndrome and hearing loss (Roux et al., 2006; Jaijo et al., 2010; Bonnet et al., 2011; Bujakowska et al., 2014). However, in these reports the variant was either observed with no other CDH23 variants or with other variants which were determined to be the cause of the patient's phenotype, and was often described as non-pathogenic. Additionally, the variant has been observed in cis with D1341N (Cremers et al., 2007). However, the variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
GeneReviews RCV000221834 SCV000268753 likely pathogenic Usher syndrome, type 1 2016-05-19 no assertion criteria provided literature only

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