ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1126A>G (p.Met376Val) (rs863224967)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201123 SCV000255675 likely pathogenic Charcot-Marie-Tooth disease, type 2A2A 2015-05-28 criteria provided, single submitter clinical testing
Invitae RCV000793093 SCV000932432 pathogenic Charcot-Marie-Tooth disease, type 2 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 376 of the MFN2 protein (p.Met376Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Charcot-Marie-Tooth disease, type 2 (PMID: 19889647, 22926664, 24473995, 26801520, 22492563, 22851605) or distal hereditary motor neuropathy (PMID: 28251916). ClinVar contains an entry for this variant (Variation ID: 217161). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Met376 amino acid residue in MFN2 have been observed in affected individuals (PMID: 22492563, 16762064, 16835246, 24957169, 21258814). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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