ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.5647A>C (p.Asn1883His) (rs747488431)

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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 RCV000725133 SCV000334353 uncertain significance not provided 2015-09-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334297 SCV000363805 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 RCV000402494 SCV000363806 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.
Illumina Clinical Services Laboratory,Illumina RCV000300308 SCV000363807 uncertain significance CDH23-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000725133 SCV000571732 uncertain significance not provided 2016-10-04 criteria provided, single submitter clinical testing The N1883H variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N1883H variant was not observed in approximately 6,500 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 N1883H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N1883H as a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000392607 SCV000712130 uncertain significance not specified 2016-05-13 criteria provided, single submitter clinical testing The p.Asn1883His variant in CDH23 has not been previously reported in individual s with hearing loss or Usher syndrome but has been identified in 18/66692 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs747488431); however, this frequency is not high enough to rule out pathogenicity. Computational prediction tools and conservation analyses sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of this variant is uncertain.
Invitae RCV000725133 SCV001212745 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 1883 of the CDH23 protein (p.Asn1883His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs747488431, ExAC 0.03%). This variant has not been reported in the literature in individuals with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 282746). 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 C65"). 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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