DOK7 S45L - GET-Evidence

Curation:
Currentness:

DOK7 S45L

(DOK7 Ser45Leu)


Short summary

This variant was seen as a compound heterozygote (with either P376PfsX30 or P469H) in two individuals with congenital myasthenic syndromes (out of a screen of 200). Other mutations in this gene are associated with the syndrome, but there are insufficient controls to establish this variant in particular as significant.

Variant evidence
Computational 3

Gene is associated with disease, NBLOSUM100 = 4, Polyphen predicts damaging effect

Functional -
Case/Control

Case/control data isn’t significant.

See Müller JS et al. 2007 (17439981).

Familial

No familial reports.

 
Clinical importance
Severity 3

Neuromuscular disorder causing weakness. Symptoms can vary widely from mild to progressive debilitating weakness.
(“Congenital Myasthenic Syndromes”, Abicht & Lochmuller)

Treatability 4

There are standard treatments that can help, some have side effects.

See unpublished research (below).

Penetrance 5

Presumed high penetrance effect

 

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

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Congenital Myasthenic Syndromes
2 198 0 50 1.0000

 

Allele frequency

  • T @ chr4:3475166: 0.6% (58/10384) in EVS
  • T @ chr4:3444963: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.6% (58/10384)

Publications
 

Müller JS, Herczegfalvi A, Vilchez JJ, Colomer J, Bachinski LL, Mihaylova V, Santos M, Schara U, Deschauer M, Shevell M, Poulin C, Dias A, Soudo A, Hietala M, Aärimaa T, Krahe R, Karcagi V, Huebner A, Beeson D, Abicht A, Lochmüller H. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain. 2007 Jun;130(Pt 6):1497-506. Epub 2007 Apr 17. PubMed PMID: 17439981.

This variant was seen as a compound heterozygote (with either P376PfsX30 or P469H) in two individuals out of a screen of 200 “so far unsolved” cases of congenital myasthenic syndromes. The authors mention screening 100 control DNAs (chromosomes?); we presume the mutation was not seen once in these.

Cases/controls case+ case– control+ control– p-value odds ratio
Congenital Myasthenic Syndromes
2 198 - 50 1.0000

 

Mihaylova V, Scola RH, Gervini B, Lorenzoni PJ, Kay CK, Werneck LC, Stucka R, Guergueltcheva V, von der Hagen M, Huebner A, Abicht A, Müller JS, Lochmüller H. Molecular characterisation of congenital myasthenic syndromes in Southern Brazil. J Neurol Neurosurg Psychiatry. 2010 Sep;81(9):973-7. Epub 2010 Jun 20. PubMed PMID: 20562457.

This variant was seen compound heterozygously in 1 out of 18 families screened. The authors report “100 healthy controls were screened for each novel mutation” — because this variant was not novel (they note it was previously reported), this implies no controls were screened for the variant.

Genomes
 

hu04FD18

 

 

Other external references
 

    dbSNP
  • rs62272670
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the DOK7 gene
    Congenital Myasthenic Syndromes
    DOK7-Related Congenital Myasthenic Syndrome
    DOK7-Related Fetal Akinesia Deformation Sequence
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/DOK7
    PolyPhen-2
  • Score: 0.302 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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