ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4405A>G (p.Ile1469Val) (rs200635365)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156528 SCV000206247 uncertain significance not specified 2014-05-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ile1469Val vari ant in CDH23 has not been previously reported in individuals with hearing loss b ut has been reported in the dbSNP database without frequency information (dbSNP rs200635365). Computational prediction tools and conservation analyses suggest t hat the Ile1469Val variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. In summary, while the clinica l significance of the Ile1469Val variant is uncertain, the computational data su ggests that it is more likely to be benign.
GeneDx RCV000766640 SCV000570418 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing The I1469V variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. It is reported as a variant of uncertain significance in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000206247.2; Landrum et al., 2015). The I1469V variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I1469V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I1469V as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000778901 SCV000915308 uncertain significance Deafness, autosomal recessive 12 2017-08-08 criteria provided, single submitter clinical testing The CDH23 gene is one of at least 37 genes in which variants are known to cause autosomal recessive nonsyndromic hearing loss. The CDH23 c.4405A>G (p.Ile1469Val) missense variant has been reported in one study in which it is found in a compound heterozygous state with an intron variant in one patient with autosomal recessive nonsyndromic hearing loss (Sloan-Heggen et al. 2016). Control data are not available for this variant which is reported at a frequency of 0.00157 in the South Asian population from the Exome Aggregation Consortium. The evidence for this variant is limited, therefore the p.Ile1469Val variant is considered a variant of unknown but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000766640 SCV001225964 uncertain significance not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1469 of the CDH23 protein (p.Ile1469Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200635365, ExAC 0.2%). This variant has been observed in an individual affected with non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 179731). 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.
Illumina Clinical Services Laboratory,Illumina RCV001106863 SCV001263972 uncertain significance Usher syndrome type 1D 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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