ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1127T>C (p.Met376Thr) (rs1569854342)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001049066 SCV001213100 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 376 of the MFN2 protein (p.Met376Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Charcot-Marie-Tooth disease (PMID: 16835246). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Met376 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been observed in individuals with MFN2-related conditions (PMID: 19889647, 22926664, 24473995, 26801520, 22492563, 22851605), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091328 SCV001247290 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790027 SCV000929417 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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