Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001243315 | SCV001416464 | uncertain significance | not provided | 2022-10-04 | 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 140 of the CDH23 protein (p.Arg140His). This variant is present in population databases (rs201361229, gnomAD 0.03%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25472526). ClinVar contains an entry for this variant (Variation ID: 968227). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001806083 | SCV002051140 | uncertain significance | not specified | 2023-06-20 | criteria provided, single submitter | clinical testing | Variant summary: CDH23 c.419G>A (p.Arg140His) results in a non-conservative amino acid change located in the 2nd cadherin-like repeat domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249242 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (4.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.419G>A, has been reported in the literature in a compound heterozygous individual affected with retinal disease and mild hearing loss (i.e. suspected Usher Syndrome), who carried another (VUS) missense variant in trans (Zhao_2015). This report not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23804846, 25472526). Three submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Gene |
RCV001243315 | SCV003805693 | uncertain significance | not provided | 2022-07-22 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Identified with a second CDH23 variant in an adult with retinitis pigmentosa and mild hearing loss in published literature, however the severity of hearing loss was not typical of CDH23-related disorders (Zhao et al., 2015); This variant is associated with the following publications: (PMID: 25472526) |
| Natera, |
RCV001835165 | SCV002086723 | uncertain significance | Usher syndrome type 1 | 2020-02-24 | no assertion criteria provided | clinical testing |