ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6049G>A (p.Gly2017Ser) (rs183431253)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039235 SCV000062919 likely pathogenic Rare genetic deafness 2011-11-23 criteria provided, single submitter clinical testing The Gly2017Ser variant in CDH23 has been reported in 2 probands with Usher synd rome type I and was absent from 192 control chromosomes (Oshima 2008, Roux 2006) . One of these probands was homozygous and the other was compound heterozygous w ith another pathogenic CDH23 variant. The Gly2017Ser variant occurs in the last base of the exon. This position has been shown to be part of the splicing consen sus sequence and splicing prediction models predict that this variant could affe ct splicing. In summary, this variant is likely to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763216 SCV000893842 likely pathogenic Deafness, autosomal recessive 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2018-10-31 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376240 SCV001573313 uncertain significance Usher syndrome type 1D 2021-04-08 criteria provided, single submitter research The CDH23 c.6049G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Invitae RCV001377826 SCV001575261 likely pathogenic not provided 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2017 of the CDH23 protein (p.Gly2017Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 46 of the CDH23 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs183431253, ExAC 0.03%). This variant has been observed in individuals affected with CDH23-related conditions (PMID: 18323324, 25404053). ClinVar contains an entry for this variant (Variation ID: 46000). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23451239). 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.
GeneDx RCV001377826 SCV001812919 likely pathogenic not provided 2021-07-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging splicing effect with skipping of exon 46 likely resulting in nonsense-mediated decay (Aparisi et al., 2013); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32488467, 23451239, 16679490, 27535533, 18429043, 25404053, 18323324, 25525159)
Clinical Genetics,Academic Medical Center RCV001377826 SCV001921507 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001377826 SCV001953094 likely pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.