Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000798323 | SCV000937933 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2024-09-17 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the MFN2 protein (p.His165Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant Charcot-Marie-Tooth disease (internal data). ClinVar contains an entry for this variant (Variation ID: 644415). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. This variant disrupts the p.His165 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16087932, 16714318, 16835246, 20951041). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |