ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.3262G>A (p.Val1088Met) (rs200632520)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039145 SCV000062829 uncertain significance not specified 2018-05-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val1088Met va riant in CDH23 has been previously reported in two probands with hearing loss by our laboratory. However, it also has been identified in 0.2% (40/18854) of Eas t Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs200632520). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. This variant has also been reported in ClinVar (Variation ID 45912; Illumi na - VUS). Computational prediction tools and conservation analysis suggest that the p.Val1088Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical si gnificance of the p.Val1088Met variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting.
Illumina Clinical Services Laboratory,Illumina RCV000285498 SCV000363692 uncertain significance CDH23-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000324074 SCV000363693 uncertain significance Usher syndrome type 1D 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000376393 SCV000363694 uncertain significance Deafness, autosomal recessive 12 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics,Fulgent Genetics RCV000764914 SCV000896077 uncertain significance Deafness, autosomal recessive 12; Usher syndrome type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001041387 SCV001205000 uncertain significance not provided 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1088 of the CDH23 protein (p.Val1088Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs200632520, ExAC 0.1%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 45912). 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.

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