ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.7145G>A (p.Arg2382Gln)

gnomAD frequency: 0.00001  dbSNP: rs759439688
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000592322 SCV000702939 uncertain significance not provided 2016-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002232558 SCV002511869 uncertain significance not specified 2022-04-07 criteria provided, single submitter clinical testing Variant summary: CDH23 c.7145G>A (p.Arg2382Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249240 control chromosomes, predominantly at a frequency of 0.00067 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (6.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.7145G>A has been reported in the literature as a compound heterozygous or non-informative (second allele not specified) genotype predominantly in East Asian cohorts with deafness/non-syndromic hearing loss (NSHL) and no reported family history (example, Miyagawa_2013, Jung_2017, Yuan_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
3billion RCV002283493 SCV002572677 likely benign Autosomal recessive nonsyndromic hearing loss 12 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.24; 3Cnet: 0.21). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CDH23-related disorder (PMID: 23967202). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002483589 SCV002785194 uncertain significance Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2021-08-13 criteria provided, single submitter clinical testing
Invitae RCV000592322 SCV003520400 uncertain significance not provided 2022-07-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2382 of the CDH23 protein (p.Arg2382Gln). This variant is present in population databases (rs759439688, gnomAD 0.07%). This missense change has been observed in individual(s) with deafness (PMID: 23967202, 28383030, 31541171). ClinVar contains an entry for this variant (Variation ID: 498100). 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 C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Baylor Genetics RCV003471953 SCV004210587 likely pathogenic Pituitary adenoma 5, multiple types 2023-10-26 criteria provided, single submitter clinical testing

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