Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000796767 | SCV000936294 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2018-12-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 259 of the MFN2 protein (p.Arg259Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Charcot-Marie-Tooth disease (PMID: 19350291). 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. This variant disrupts the p.Arg259 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been observed in individuals with MFN2-related conditions (PMID: 25957633, 24450158, 22492563, 24863639, 24627108), suggesting that it is a clinically significant residue. As a result, 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 | RCV000789362 | SCV000928717 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |