ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.313A>G (p.Thr105Ala) (rs1553142428)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000653940 SCV000775830 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 105 of the MFN2 protein (p.Thr105Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with autosomal dominant Charcot-Marie-Tooth disease (PMID: 22492563, Invitae). ClinVar contains an entry for this variant (Variation ID: 543234). 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. This variant disrupts the p.Thr105 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15064763, 16043786, 16835246, 17296794, 17959936, 24957169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000790041 SCV000929431 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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