ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.5734C>T (p.Arg1912Trp)

gnomAD frequency: 0.00008  dbSNP: rs397517344
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Total submissions: 4
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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 RCV000039226 SCV000062910 uncertain significance not specified 2012-03-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg1912Trp vari ant in CDH23 was identified as a homozygous variant in a patient who was also ho mozygous for the Gly2017Ser variant (Oshima 2008). This suggests that the two v ariants are in cis as observed in this family. Computational analyses (biochemic al amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide s trong support for or against pathogenicity and given the predicted splice impact of the Gly2017Ser variant, the Arg1912Trp variant may not contribute to pathoge nicity of the allele. In summary, the clinical significance of this variant in i solation cannot be determined with certainty; however, the allele containing thi s variant and Gly2017Ser, is still likely pathogenic.
Invitae RCV001241540 SCV001414563 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1912 of the CDH23 protein (p.Arg1912Trp). This variant is present in population databases (rs397517344, gnomAD 0.005%). 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: 45991). 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.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375123 SCV001572036 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PP3_Supporting
Natera, Inc. RCV001826575 SCV002092510 uncertain significance Usher syndrome type 1 2020-07-13 no assertion criteria provided clinical testing

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