ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.7823G>A (p.Arg2608His) (rs202052174)

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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 RCV000039276 SCV000062960 uncertain significance not specified 2018-12-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg2608His va riant in CDH23 has been reported in 0.1% (7/6982) of chromosomes from probands w ith either hearing loss or Usher syndrome, at least one of whom had an alternate genetic cause for their disease (Astuto 2002, Jaijo 2010; Malm 2011, LMM data). However, this variant has also been identified in 0.1% (116/115288) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which suggests that t he variant is unlikely to be causative for disease. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, while the clinical significance of p.Arg2608His is uncertain, these data suggest that it is more likely benign. ACMG/AMP criteria: BS1_Supporting, PP3.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725220 SCV000335098 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000039276 SCV000577108 likely benign not specified 2017-12-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000778289 SCV000914467 uncertain significance CDH23-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The CDH23 c.7823G>A (p.Arg2608His) missense variant has been reported in at least three studies in individuals with autosomal recessive nonsyndromic hearing loss, in which it is found in a total of 25 individuals, including in three in a compound heterozygous state and in 22 in a heterozygous state (Astuto et al. 2002; Wu et al. 2016). The p.Arg2608His variant is also reported in one study in a compound heterozygous state in an individual with Usher syndrome (Jaijo et al. 2010). The p.Arg2608His variant was absent from 256 controls, but is reported at a frequency of 0.00213 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2608His 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.
Mendelics RCV000988383 SCV001138082 uncertain significance Retinitis pigmentosa-deafness syndrome 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000725220 SCV001413566 uncertain significance not provided 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2608 of the CDH23 protein (p.Arg2608His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs202052174, ExAC 0.2%). This variant has been observed in individuals affected with deafness or Usher syndrome (PMID: 12075507, 19683999). ClinVar contains an entry for this variant (Variation ID: 46040). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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