ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6050-9G>A (rs367928692)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239237 SCV000297306 pathogenic not provided 2015-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763217 SCV000893843 pathogenic Deafness, autosomal recessive 12; Usher syndrome, type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000239237 SCV000329238 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing The c.6050-9 G>A splice site variant in the CDH23 gene has been reported previously in association with Usher syndrome type ID (von Brederlow et al., 2002; Besnard et al., 2014), using alternate nomenclature as IVS45-9 G>A. Von Brederlow and colleagues report on several patients who are heterozygous for this variant, and one who is homozygous. The G>A substitution is predicted to create a novel acceptor splice site 9 bp upstream from the 5' end of exon 46, which results in an insertion of 7 bp at the 3' end of intron 45. The c.6050-9 G>A 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. Given the available evidence, we interpret c.6050-9 G>A as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039236 SCV000062920 pathogenic Rare genetic deafness 2015-02-03 criteria provided, single submitter clinical testing The c.6050-9G>A variant in CHD23 has been reported in >20 individuals with Usher syndrome who were homozygous or compound heterozygous for the variant. The vari ant segregated with disease in 3 affected relatives from 3 families (von Brederl ow 2002, Astuto 2002, Pennings 2004, Roux 2006, Ebermann 2007, Oshima 2008, Jaij o 2009, Vache 2010, Kimberling 2010, Bonnet 2011, Roux 2011, Schultz 2011, Besna rd 2014). This variant has been identified in 3/28260 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs36 7928692). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. This v ariant is located in the 3' splice region. In vitro functional studies provide e vidence that the c.6050-9G>A variant impacts splicing (Von Brederlow 2002, Vache 2010). In summary, this variant meets our criteria to be classified as pathogen ic for Usher syndrome in an autosomal recessive manner. ACMG/AMP codes applied: PM3_VeryStrong; PM2; PS3_Moderate; PP4.

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