MFN2 R707W - GET-Evidence

Curation:
Currentness:

MFN2 R707W

(MFN2 Arg707Trp)


Short summary

Reported to cause Charcot-Marie-Tooth disease type 2 in a recessive manner, causing peripheral neuropathy and clubfoot. Insufficient observations to establish statistical significance for this particular variant, but other variants in this gene are well-established as causal.

Variant evidence
Computational 2

Other mutations in this gene cause the disease, Polyphen 2 predicts damaging effect

Functional -
Case/Control

Insufficient data to establish statistical significance for this variant

Familial -
 
Clinical importance
Severity 4
Treatability 2

Some circumstances to avoid (drugs that exacerbate symptoms)

Penetrance 5
 

Impact

High clinical importance, Uncertain pathogenic

(The "high clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr1:12069698: 0.0% (2/10758) in EVS
  • Frequency shown in summary reports: 0.0% (2/10758)

Publications
 

Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, Vallat JM, Ouvrier RA. Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology. 2008 May 6;70(19):1678-81. doi: 10.1212/01.wnl.0000311275.89032.22. PubMed PMID: 18458227.

Three families with homozygous or compound heterozygous MFN2 mutations were examined (the authors do not describe how many were screened to discover these families). The third patient described is homozygous for this variant (R707W).

The summary currently presented in OMIM (as of 1/2013) appears to be mistaken in its understanding of the paper. It states: “Each parent was heterozygous for the mutation and showed a mild form of peripheral neuropathy. Nicholson et al. (2008) noted that the apparent autosomal recessive inheritance of the disorder in this family was actually semidominant and that the parents showed incomplete penetrance.”

In fact, the authors discuss the combined effect of the two mutations in an attempt to explain why the parents were not symptomatic despite carrying mutations: they attempt an “explanation for the parents being asymptomatic or very mildly symptomatic despite carrying heterozygous mutations”. Elsewhere the parents are all described as “asymptomatic” and with “minimal clinical findings of neuropathy and minor electrophysiologic evidence of neuropathy”. This is all consistent with arguing for a recessive mode of inheritance.

Calvo J, Funalot B, Ouvrier RA, Lazaro L, Toutain A, De Mas P, Bouche P, Gilbert-Dussardier B, Arne-Bes MC, Carrière JP, Journel H, Minot-Myhie MC, Guillou C, Ghorab K, Magy L, Sturtz F, Vallat JM, Magdelaine C. Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Arch Neurol. 2009 Dec;66(12):1511-6. doi: 10.1001/archneurol.2009.284. PubMed PMID: 20008656.

A survey of of 107 unrelated patients with type 2 Charcot-Marie-Tooth disease and 43 “median” cases (type 1, but close to the threshold motor nerve conduction velocity used to separate types). Three patients from one family were found to be compound heterozygous for this variant and G108R. The authors report that the parents (each carrying one of these variants) show no symptoms of neuropathy and had normal electroneuromyographic findings.

Genomes
 

Other external references
 

    GeneTests
  • GeneTests records for the MFN2 gene
    Charcot-Marie-Tooth Neuropathy Type 2
    Charcot-Marie-Tooth Neuropathy Type 2A
    Charcot-Marie-Tooth Neuropathy Type 2A2
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MFN2
    PolyPhen-2
  • Score: 0.991 (probably damaging)
    Web search results (0 hits -- see all)

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in