ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val) (rs111033536)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001261015 SCV001438402 uncertain significance Usher syndrome 2020-09-22 reviewed by expert panel curation The c.9569C>T (p.Ala3190Val) variant in CDH23 was identified in 0.054% (69/127,854) of non-Finnish Europeans alleles in gnomAD v2 (PM2_Supporting). This variant has been observed in 1 proband diagnosed with Usher syndrome; however, the other variant was not confirmed (PMID: 25404053). It was also reported in 1 proband with nonsyndromic hearing loss who carried another VUS missense variant with phase unknown (PMID: 27068579). However, the p.Ala3190Val variant has been seen in the homozygous state in 1 reportedly unaffected parent (BS2; Invitae internal data, ClinVar SCV001110059.2). The REVEL computational prediction tool produced a score of 0.836, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS2, PM2_Supporting, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039313 SCV000062997 uncertain significance not specified 2017-09-12 criteria provided, single submitter clinical testing The p.Ala3190Val variant in CDH23 has been reported in 1 individual with Usher s yndrome who also had a duplication of exon 29 in CDH23 that is of uncertain sign ificance (Aparisi 2014), and in 1 individual with hearing loss who also had the p.Arg3206Cys variant of uncertain significance in CDH23 (Sommen 2016). The p.Ala 3190Val variant has also been identified by our laboratory in the heterozygous s tate in 3 individuals with hearing loss; however, a variant affecting the remain ing copy of CDH23 was not identified in any of these individuals. This variant h as been identified in 0.08% (8/10122) of Ashkenazi Jewish chromosomes and 0.05% (64/126200) European chromosomes by Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs111033536). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Ala3190Val variant is uncertain.
GeneDx RCV000766715 SCV000564847 uncertain significance not provided 2021-09-23 criteria provided, single submitter clinical testing Identified in a patient with nonsyndromic hearing loss, along with a second variant with unknown phase in published literature (Sommen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 32387678, 30245029, 27068579, 25404053)
Fulgent Genetics,Fulgent Genetics RCV000763669 SCV000894549 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 RCV000779032 SCV000915480 uncertain significance CDH23-Related Disorders 2017-12-05 criteria provided, single submitter clinical testing The CDH23 c.9569C>T (p.Ala3190Val) missense variant has been reported in two studies in which it is identified in a compound heterozygous state in two individuals, one with a diagnosis of Usher syndrome and one with autosomal recessive nonsyndromic hearing loss (Aparisi et al. 2014; Sommen et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence, the p.Ala3190Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000766715 SCV001110059 benign not provided 2020-12-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766715 SCV001246549 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375340 SCV001572058 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Moderate, PM2_Moderate, PP3_Supporting

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