ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.8G>A (p.Arg3His)

gnomAD frequency: 0.00001  dbSNP: rs397517363
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039299 SCV000062983 uncertain significance not specified 2019-06-26 criteria provided, single submitter clinical testing The p.Arg3His variant in CDH23 has been previously reported by our laboratory with one individual with hearing loss and delayed walking. This individual also harbored a second variant of uncertain significance in CDH23, but testing of parents to determine phasing was not performed. The p.Arg3His variant has been identified 0.02% (6/23796) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Invitae RCV001248760 SCV001422269 uncertain significance not provided 2022-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3 of the CDH23 protein (p.Arg3His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 46063). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. 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.
Natera, Inc. RCV001831680 SCV002086114 uncertain significance Usher syndrome type 1 2019-10-28 no assertion criteria provided clinical testing

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