ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1091G>A (p.Arg364Gln) (rs879254011)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235416 SCV000293161 pathogenic not provided 2015-09-28 criteria provided, single submitter clinical testing The R364Q pathogenic variant in the MFN2 gene has been identified previously in individuals with CMT2A (Calvo et al., 2009; Loiseau et al., 2007). Different amino acid substitutions at the same position (R364P; R364W) have also been reported in association with CMT2 (Bombelli et al., 2014; Calvo et al., 2009; Chung et al., 2006; Feely et al., 2011; Gowrisankaran et al., 2011; Lin et al., 2011; Rouzier et al., 2012; Saporta et al., 2015; Zuchner et al., 2006). Additionally, multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with MFN2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R364Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species.
Invitae RCV000463885 SCV000547936 pathogenic Charcot-Marie-Tooth disease, type 2 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 364 of the MFN2 protein (p.Arg364Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease type 2A (PMID: 20008656, 17444508, 18996695, 22492563, 19889647). ClinVar contains an entry for this variant (Variation ID: 245944). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.Arg364Trp, p.Arg364Pro) have been determined to be pathogenic (PMID: 22492563, 20008656, 24957169, 16437557, 21707411). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235416 SCV001370929 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789067 SCV000928416 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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