Submissions for variant NM_022124.6(CDH23):c.9726del (p.Ser3243fs)

dbSNP: rs767176528

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001266449	SCV001444624	uncertain significance	Inborn genetic diseases	2017-11-24	criteria provided, single submitter	clinical testing
National Institute on Deafness and Communication Disorders, National Institutes of Health	RCV001328022	SCV001519355	uncertain significance	Childhood onset hearing loss	2021-07-08	criteria provided, single submitter	research	PVS1 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging.
Invitae	RCV001880118	SCV002316661	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser3243Profs*5) in the CDH23 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 112 amino acid(s) of the CDH23 protein. This variant is present in population databases (rs767176528, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 985511). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469367	SCV002766447	uncertain significance	not specified	2022-11-10	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.9726delC (p.Ser3243ProfsX5) results in a premature termination codon in the penultimate exon of the gene. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 112 amino acids of the protein. Downstream truncating variants have not been reported in HGMD. The variant allele was found at a frequency of 6.4e-05 in 156562 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CDH23 causing Usher Syndrome (6.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.9726delC has been reported in the literature in one individual affected with hearing loss, however, variants in other genes known to be associated with hearing loss were also identified (Adeyemo_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003473844	SCV004210627	uncertain significance	Pituitary adenoma 5, multiple types	2023-08-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830068	SCV002086331	uncertain significance	Usher syndrome type 1	2020-01-16	no assertion criteria provided	clinical testing