ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.2959G>A (p.Asp987Asn)

gnomAD frequency: 0.00002  dbSNP: rs770665588
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001339975 SCV001533760 uncertain significance not provided 2021-08-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 987 of the CDH23 protein (p.Asp987Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs770665588, ExAC 0.06%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 26226137; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). 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.
GeneDx RCV001339975 SCV001988124 uncertain significance not provided 2022-12-21 criteria provided, single submitter clinical testing Observed with a second CDH23 variant in an individual with hearing loss in published literature (Bademci et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26226137, 34652575)
King Laboratory, University of Washington RCV003155398 SCV003844197 likely pathogenic Autosomal recessive nonsyndromic hearing loss 12 2023-02-28 criteria provided, single submitter research This variant occurred in compound heterozygosity with a CDH23 frameshift variant in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, this patient did not have any known visual impairment (age 6y). This patient's family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has not been reported to ClinVar and is not found on gnomAD. Based on compound heterozygosity with a loss-of-function variant, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Baylor Genetics RCV003473868 SCV004210633 likely pathogenic Pituitary adenoma 5, multiple types 2023-08-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003490201 SCV004240991 uncertain significance not specified 2023-12-12 criteria provided, single submitter clinical testing Variant summary: CDH23 c.2959G>A (p.Asp987Asn) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 224614 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2959G>A has been reported in the literature as a single heterozygous change in one individual affected with autosomal recessive hearing loss, without strong evidence for causality (example, Bademci_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26226137). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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