Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000532246 | SCV000657724 | pathogenic | Charcot-Marie-Tooth disease, type 2 | 2017-03-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 104 of the MFN2 protein (p.Arg104Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. It also falls at the last nucleotide of exon 4 of the MFN2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 22492563). ClinVar contains an entry for this variant (Variation ID: 214651). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg104Trp) has been determined to be pathogenic (PMID: 26307494, 18425620). 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. |
EGL Genetic Diagnostics, |
RCV000711275 | SCV000705951 | uncertain significance | not provided | 2017-04-07 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics Inc | RCV000711275 | SCV000841611 | uncertain significance | not provided | 2018-05-17 | criteria provided, single submitter | clinical testing | |
Inherited Neuropathy Consortium | RCV000789063 | SCV000928412 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |