ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.730G>A (p.Val244Met) (rs879253777)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235053 SCV000292342 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2015-08-18 criteria provided, single submitter research This variant has been previously reported as disease-causing and was found in one patient with demyelinating neuropathy and one patient with axonal neuropathy
Invitae RCV000693266 SCV000821127 pathogenic Charcot-Marie-Tooth disease, type 2 2019-07-02 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 244 of the MFN2 protein (p.Val244Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 15549395, 20008656). This variant has also been shown to be de novo in affected individuals (PMID: 26257172, Invitae). ClinVar contains an entry for this variant (Variation ID: 243066). 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 C15"). A different missense substitution at this codon (p.Val244Leu) has been determined to be likely pathogenic (PMID: 26378787, 26257172). This suggests that the valine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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