Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001208639 | SCV001380038 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2019-08-29 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with aspartic acid at codon 165 of the MFN2 protein (p.His165Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal dominant Charcot-Marie-Tooth disease with pyramidal features in a large family (PMID: 16087932). ClinVar contains an entry for this variant (Variation ID: 2275). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.His165 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16835246, 16714318, 24819634, 17309650, 24126688, 27549087). 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. |
| OMIM | RCV000002363 | SCV000022521 | pathogenic | Charcot-Marie-Tooth disease, type 2A2A | 2005-08-09 | no assertion criteria provided | literature only | |
| Inherited Neuropathy Consortium | RCV000789416 | SCV000928771 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |