Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001237586 | SCV001410352 | uncertain significance | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency | 2022-09-27 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 613 of the DNMT3B protein (p.Val613Leu). This variant is present in population databases (rs768347895, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DNMT3B-related conditions. ClinVar contains an entry for this variant (Variation ID: 963548). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNMT3B protein function. This variant disrupts the p.Val613 amino acid residue in DNMT3B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17893117, 17908720). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |