ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.752C>G (p.Pro251Arg) (rs1557525153)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700405 SCV000829158 likely pathogenic Charcot-Marie-Tooth disease, type 2 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 251 of the MFN2 protein (p.Pro251Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Charcot-Marie-Tooth disease (PMID: 21508331, 21258814). 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.Pro251 amino acid residue in MFN2 have been observed in affected individuals (PMID: 24078732, 15064763, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inherited Neuropathy Consortium RCV000789692 SCV000929068 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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