Submissions for variant NM_014874.4(MFN2):c.2240T>G (p.Met747Arg)

dbSNP: rs879254059

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236805	SCV000293332	uncertain significance	not provided	2016-10-17	criteria provided, single submitter	clinical testing	The M747R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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 M747R 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 position that is conserved across species. A different missense variant in the same codon (M747T) as well as missense variants in nearby residues (S743R, L745P, H750P) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease type 2 (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300263	SCV001489400	uncertain significance	Charcot-Marie-Tooth disease type 2	2020-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with arginine at codon 747 of the MFN2 protein (p.Met747Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 28660751). ClinVar contains an entry for this variant (Variation ID: 246039). 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.Met747 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been observed in individuals with MFN2-related conditions (PMID: 20008656), which suggests that this may be a clinically significant amino acid residue. 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.