ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4391C>T (p.Ala1464Val) (rs374362883)

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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 RCV000039181 SCV000062865 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala1464Val va riant in CDH23 has been reported in 2 individuals with hearing loss; however in 1 of these individuals had an alternate etiology of the hearing loss identified (Shearer 2013, LMM unpublished data). This variant has also been identified in 0.03% (41/125814) of European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org/; dbSNP rs374362883); however, its freque ncy is not high enough to rule out a pathogenic role. The alanine (Ala) at posi tion 1464 is not conserved in mammals or evolutionary distant species, with 1 ma mmal (gibbon) having a valine (Val), supporting that a change at this position c ould be tolerated. Additional computational prediction tools and conservation an alyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ala1464Val variant is uncerta in, the conservation data suggests that it is more likely to be benign.
Fulgent Genetics,Fulgent Genetics RCV000764918 SCV000896081 uncertain significance Deafness, autosomal recessive 12; Usher syndrome type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001106861 SCV001263970 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 RCV001106862 SCV001263971 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.
Invitae RCV001244548 SCV001417776 uncertain significance not provided 2019-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1464 of the CDH23 protein (p.Ala1464Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs374362883, ExAC 0.03%), including at least one homozygous and/or hemizygous individual. This variant has been observed in an individual affected with non-syndromic hearing loss (PMID: 23804846). ClinVar contains an entry for this variant (Variation ID: 45947). 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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