ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.3022G>A (p.Val1008Met) (rs201053044)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723774 SCV000202377 uncertain significance not provided 2014-02-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000402667 SCV000363677 uncertain significance Usher syndrome type 1D 2018-01-13 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 RCV000283445 SCV000363678 uncertain significance Deafness, autosomal recessive 12 2018-01-13 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.
GeneDx RCV000723774 SCV000572172 uncertain significance not provided 2016-11-13 criteria provided, single submitter clinical testing The V1008M variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6400 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 V1008M 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 where amino acids with similar properties to Valine are tolerated 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 V1008M as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764913 SCV000896076 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 RCV000723774 SCV001089392 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195485 SCV001365862 uncertain significance not specified 2019-07-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val1008Met variant in CDH23 has not been previously reported in individuals with hearing loss, but was reported in ClinVar (Variation ID 166811). This variant was also identified in several populations in gnomAD, with the highest allele frequency observed in 0.25% (25/10040) of Ashkenazi Jewish chromosomes (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.

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