Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000700272 | SCV000829020 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2019-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 259 of the MFN2 protein (p.Arg259His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs755065651, ExAC 0.001%). This variant has been observed in several individuals affected with Charcot-Marie-Tooth disease and to segregate with Charcot-Marie-Tooth disease in a family (PMID: 24450158, 24863639, 24627108, 26989944). ClinVar contains an entry for this variant (Variation ID: 577496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg259 amino acid residue in MFN2 have been observed in affected individuals (PMID: 22492563, 24957169, 25802885, 25957633, 19350291). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| Inherited Neuropathy Consortium | RCV000789388 | SCV000928743 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |