ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.2230G>A (p.Glu744Lys) (rs1064794571)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486011 SCV000569482 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing The E744K variant has been previously reported in a Korean family with CMT2; however, no further information was provided regarding segregation and other causes of CMT were not ruled out (Choi et al., 2015). The E744K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E744K 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000698484 SCV000827150 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 744 of the MFN2 protein (p.Glu744Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease, type 2 (PMID: 24863639). ClinVar contains an entry for this variant (Variation ID: 420586). 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"). A different missense substitution at this codon (p.Glu744Met) has been reported in an individual affected with Charcot-Marie-Tooth disease, type 2 (PMID: 22206013). 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 RCV001027466 SCV001190034 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided provider interpretation

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