Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000604516 | SCV000713735 | uncertain significance | not specified | 2017-12-05 | criteria provided, single submitter | clinical testing | The p.Arg526Cys variant in TBC1D24 has not been previously reported in individua ls with hearing loss. This variant has been identified in 5/22404 Finnish chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs767145914). Although this variant has been seen in the general popul ation, its frequency is not high enough to rule out a pathogenic role. Computati onal prediction tools and conservation analysis suggest that the p.Arg526Cys var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg526C ys variant is uncertain. ACMG/AMP Criteria applied: PP3. |
Invitae | RCV001868032 | SCV002253180 | uncertain significance | Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 526 of the TBC1D24 protein (p.Arg526Cys). This variant is present in population databases (rs767145914, gnomAD 0.02%). 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. 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 expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 506193). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. |