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

gnomAD frequency: 0.00006  dbSNP: rs367928692

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
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	2023-06-15	criteria provided, single submitter	clinical testing	Published in vivo and in vitro studies demonstrate abnormal gene splicing with an insertion of a 7bp intronic sequence, leading to absence of expression (Vache et al., 2010; Valero et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25404053, 11857743, 31546658, 32467589, 24498627, 20513143, 21940737, 30303587, 31980526, 35020051)
Fulgent Genetics, Fulgent Genetics	RCV000763217	SCV000893843	pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239237	SCV001389693	pathogenic	not provided	2024-01-20	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs367928692, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome (PMID: 11857743, 12075507, 17407589, 18429043, 21569298, 21940737, 25404053). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS45-9G>A. ClinVar contains an entry for this variant (Variation ID: 46001). Studies have shown that this variant results in insertion of 7 nucleotides from intron 46 and introduces a premature termination codon (PMID: 11857743, 20513143). The resulting mRNA is expected to undergo nonsense-mediated decay. 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
Baylor Genetics	RCV003473281	SCV004210578	pathogenic	Pituitary adenoma 5, multiple types	2024-03-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814961	SCV005072415	pathogenic	Retinal dystrophy	2022-01-01	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	Hearing loss, autosomal recessive		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000239237	SCV001924494	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000239237	SCV001959225	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000239237	SCV001975840	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757123	SCV005360046	pathogenic	CDH23-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The CDH23 c.6050-9G>A variant is predicted to interfere with splicing. This variant has been reported to be causative for nonsyndromic hearing loss and Usher syndrome (von Brederlow et al. 2002. PubMed ID: 11857743; Aparisi et al. 2014. PubMed ID: 25404053; Besnard et al. 2014. PubMed ID: 24498627). In vitro characterization indicates that this variant creates a novel acceptor site and results in a frameshift causing addition of seven nucleotides in exon 46 (Valero et al. 2019. PubMed ID: 31546658). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.