ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.809T>C (p.Met270Thr) (rs771996573)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236640 SCV000294076 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing The M270T variant was previously identified in an individual with Charcot-Marie-Tooth disease type 2; however, two other MFN2 variants were also identified in this individual (Antoniadi et al., 2015). The M270T 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. The M270T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a conserved position predicted to be within the GTPase domain of the MFN2 protein (Choi et al., 2015). Missense variants in nearby residues (V273G, R274Q) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease type 2A (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000818378 SCV000958988 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-03-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 270 of the MFN2 protein (p.Met270Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs771996573, ExAC 0.006%). This variant has not been reported in the literature in individuals with MFN2-related disease. ClinVar contains an entry for this variant (Variation ID: 246495). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium RCV001027467 SCV001190035 likely benign Charcot-Marie-Tooth disease no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.