ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.2218T>A (p.Trp740Arg)

dbSNP: rs1557539004
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000693444 SCV000821314 uncertain significance Charcot-Marie-Tooth disease type 2 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 740 of the MFN2 protein (p.Trp740Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). A different variant giving rise to the same protein effect (c.2218T>C, p.Trp740Arg) has been observed in a family affected with Charcot-Marie-Tooth disease Type 2A2 (PMID: 22762946, 26382835). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Trp740 amino acid residue in MFN2 has been determined to be clinically significant (PMID:  15064763, 24126688, 20008656). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.

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