ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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,; 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239237 SCV000297306 pathogenic not provided 2015-08-10 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.
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
Invitae RCV000239237 SCV001389693 pathogenic not provided 2020-09-21 criteria provided, single submitter clinical testing This sequence change falls in intron 46 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. This variant is present in population databases (rs367928692, ExAC 0.02%). This variant has been reported to segregate with Usher syndrome type I in several families (PMID: 11857743, 21940737). This variant has also been reported as homozygous or in combination with another CDH23 variant in many individuals with Usher syndrome type I (PMID: 11857743, 25404053, 18429043, 21569298, 12075507, 17407589). ClinVar contains an entry for this variant (Variation ID: 46001). This variant is also known as IVS45-9G>A in the literature. Experimental studies have shown that this intronic change results in aberrant splicing (PMID: 11857743, 20513143). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000239237 SCV001446876 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV001274898 SCV001459451 pathogenic Usher syndrome type 1 2020-09-16 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291215 SCV001479640 likely pathogenic Autosomal recessive nonsyndromic deafness no assertion criteria provided research

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