Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000188095 | SCV000241699 | uncertain significance | not provided | 2017-07-26 | criteria provided, single submitter | clinical testing | p.Pro753Thr (CCT>ACT): c.2257 C>A in exon 9 of the MBD5 gene (NM_018328.4) The P753T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P753T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P753T 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 mammals. However, to our knowledge, only deletions and frameshift mutations in MBD5 have been published in association with epilepsy. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Labcorp Genetics |
RCV000686657 | SCV000814185 | uncertain significance | Intellectual disability, autosomal dominant 1 | 2023-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 753 of the MBD5 protein (p.Pro753Thr). This variant is present in population databases (rs370340010, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 206083). 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 MBD5 protein function with a negative predictive value of 80%. 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. |