Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479322 | SCV000573625 | uncertain significance | not provided | 2017-03-06 | criteria provided, single submitter | clinical testing | The R294W variant in the TBCD gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R294W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R294W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R294W as a variant of uncertain significance. |
| Fulgent Genetics, |
RCV000764151 | SCV000895148 | uncertain significance | Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000479322 | SCV003021708 | pathogenic | not provided | 2023-09-15 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 423874). 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 TBCD protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 32705489). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 294 of the TBCD protein (p.Arg294Trp). |