ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.1127T>C (p.Met376Thr)

dbSNP: rs1569854342
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001049066 SCV001213100 likely pathogenic Charcot-Marie-Tooth disease type 2 2021-06-24 criteria provided, single submitter clinical testing This variant disrupts the p.Met376 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19889647, 22926664, 24473995, 26801520, 22492563). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function. This variant has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth (PMID: 16835246). ClinVar contains an entry for this variant (Variation ID: 637733). This variant is not present in population databases (ExAC no frequency). 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. 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.
CeGaT Center for Human Genetics Tuebingen RCV001091328 SCV001247290 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001091328 SCV001880472 uncertain significance not provided 2020-11-17 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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