ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 250 of the MFN2 protein (p.Arg250Gln). This variant is present in population databases (rs140234726, gnomAD 0.04%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21258814, 22492563, 25850958, 26930221, 32376792). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant shows reduced penetrance with mild disease symptoms, later onset and some individuals may be asymptomatic (PMID: 26930221, 25850958). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214653). 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 MFN2 protein function. This variant disrupts the p.Arg250 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16714318, 26306937, 28660751, 35922214). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the MFN2 gene, it has been classified as Pathogenic (low penetrance).