ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.776G>A (p.Arg259His) (rs755065651)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700272 SCV000829020 pathogenic Charcot-Marie-Tooth disease, type 2 2019-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 259 of the MFN2 protein (p.Arg259His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs755065651, ExAC 0.001%). This variant has been observed in several individuals affected with Charcot-Marie-Tooth disease and to segregate with Charcot-Marie-Tooth disease in a family (PMID: 24450158, 24863639, 24627108, 26989944). ClinVar contains an entry for this variant (Variation ID: 577496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg259 amino acid residue in MFN2 have been observed in affected individuals (PMID: 22492563, 24957169, 25802885, 25957633, 19350291). 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.
Inherited Neuropathy Consortium RCV000789388 SCV000928743 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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