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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