Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001064640 | SCV001229551 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2019-03-26 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with proline at codon 92 of the MFN2 protein (p.Leu92Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Charcot-Marie-Tooth disease and was observed to be de novo in at least one case (PMID: 16835246, 16714318). 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.Leu92 amino acid residue in MFN2. Other variant(s) that disrupt this residue (p.Leu92Arg) have been determined to be pathogenic (PMID: 21258814). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Inherited Neuropathy Consortium | RCV000790024 | SCV000929414 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |