ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4210-2A>G

dbSNP: rs557620034
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000710062 SCV000840447 pathogenic Usher syndrome type 1D; Autosomal recessive nonsyndromic hearing loss 84A 2016-09-21 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003141715 SCV003823082 likely pathogenic not provided 2022-11-30 criteria provided, single submitter clinical testing
Baylor Genetics RCV003472256 SCV004212339 likely pathogenic Pituitary adenoma 5, multiple types 2023-01-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003141715 SCV004398873 likely pathogenic not provided 2023-07-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 34 of the CDH23 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH23 are known to be pathogenic (PMID: 11138009, 21940737). This variant is present in population databases (rs557620034, gnomAD 0.007%). 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: 585306). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV004026789 SCV004921994 uncertain significance Inborn genetic diseases 2024-01-03 criteria provided, single submitter clinical testing The c.4210-2A>G intronic variant results from an A to G substitution two nucleotides before exon 35 (coding exon 34) of the CDH23 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/249274) total alleles studied. The highest observed frequency was 0.007% (1/15490) of African alleles. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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