ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.8083G>A (p.Asp2695Asn)

gnomAD frequency: 0.00002  dbSNP: rs369501114
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089682 SCV001245166 uncertain significance Nonsyndromic genetic hearing loss 2023-06-26 reviewed by expert panel curation The c.8083G>A variant in CDH23 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 2695 (p.Asp2695Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005% (4/74190) in European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007]) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.789, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in a total of three individuals with phenotypes consistent with CDH23-related disorders. One individual with hearing loss was compound heterozygous for the variant and a pathogenic variant, however phase was unknown (c.6085C>T p.Arg2029Trp , 0.5 PM3 points, PMID: 35020051). The second individual was a one-year-old female with hearing loss who harbored the c.6866A>G p.Asn2289Ser variant of uncertain significance in trans (0.25 PM3 points, ARUP internal data SCV000602953.1). The third individual had hearing loss and retinopathy, which is highly specific for Usher syndrome,, and harbored the c.7225-1G>A variant of uncertain significance in trans (0.25 PM3 points, PP4, PMID: 30081015). This individual also had seizures, developmental delay, and ADHD and a de novo ANKRD11 variant thought to cause these additional features. In summary, this variant has been classified as uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PP3, PP4, PM3. (VCEP specifications version 2; 06.26.2023).
GeneDx RCV000485626 SCV000571792 likely pathogenic not provided 2022-11-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 30081015, 35020051)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507978 SCV000602953 uncertain significance not specified 2017-01-13 criteria provided, single submitter clinical testing
Invitae RCV000485626 SCV001209916 uncertain significance not provided 2022-07-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2695 of the CDH23 protein (p.Asp2695Asn). This variant is present in population databases (rs369501114, gnomAD 0.006%). 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: 422345). 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 C0"). 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.
New York Genome Center RCV001839003 SCV002099114 uncertain significance Usher syndrome type 1D 2021-03-26 criteria provided, single submitter clinical testing The inherited heterozygous c.8083G>A (p.Asp2695Asn) variant identified in exon 57 (of 70) of the CDH23 gene has not been reported in affected individuals in the literature. However, the variant has been reported in the ClinVar database and is classified as a variant of uncertain significance by the ClinGen Hearing Loss Variant Curation Expert Panel [ClinVar variation ID:422345]. The variant has 0.00001972 allele frequency in the gnomAD(v3) database suggesting it is not a common benign allele in the populations represented in that database. The variant affects an evolutionarily conserved reside and is predicted deleterious by multiple in silico tools [CADD score = 34, REVEL score = 0.789]. Functional studies to evaluate the potential pathogenicity of this variant have not been reported in the literature. Due to lack of compelling evidence for its pathogenicity, the inherited heterozygous c.8083G>A (p.Asp2695Asn) variant identified in the CDH23gene is reported as a variant of uncertain significance.

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