Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000693474 | SCV000821345 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2019-04-02 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with proline at codon 364 of the MFN2 protein (p.Arg364Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease, type 2 and optic atrophy in a family (PMID: 24957169) and has been reported in individuals affected with Charcot-Marie-Tooth disease, type 2 (PMID: 22492563, 20008656, 21508331). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg364Trp) has been determined to be pathogenic (PMID: 16437557, 16835246, 22492563, 21707411, 22206013, 21508331, 25802885, 28063088, 27549087, 25448007). This suggests that the arginine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |
| Inherited Neuropathy Consortium | RCV000790019 | SCV000929409 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |