MEFV E148Q - GET-Evidence

Curation:
Currentness:

MEFV E148Q

(MEFV Glu148Gln)


Short summary

Some reports believe this cause Familial Mediterranean Fever in a recessive manner with reduced penetrance (i.e. not all get the disease). However, these reports lack strong statistical significance; other studies argue the variant is not associated with the disease.

Variant evidence
Computational 1

This site is conserved across several species.

See 19820229.

Functional -
Case/Control

OR=1.2 but this is not significant. P-Value = 0.2

See Aksentijevich I et al. 1999 (10090880), 19820229.

Familial -1

See Tchernitchko DO et al. 2006 (16439437).

 
Clinical importance
Severity 3

See Gene Review.

Treatability 2

Unclear if treatment is required given the evidence for this variant.

Penetrance 4

argued to be pathogenic with reduced penetrance

See Aksentijevich I et al. 1999 (10090880).

 

Impact

Moderate clinical importance, Uncertain pathogenic

(The "moderate 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

This variant is argued by some to cause autosomal recessive Familial Mediterranean Fever with reduced penetrance, others argue that it is a polymorphism and not disease-associated.

Genetests notes that there is debate as to whether this is causal or simply a polymorphism; it might be only causal when compound heterozygous with a more pathogenic variant. Many homozygous for this are not symptomatic; they note that continuous colchicine treatment is less recommended for individuals with this, only given in case of inflammatory episodes.

Total cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
58 766 163 2639 0.2138 1.226

 

Allele frequency

  • G @ chr16:3304626: 1.2% (127/10502) in EVS
  • G @ chr16:3244626: 8.8% (10/114) in GET-Evidence
  • Frequency shown in summary reports: 1.2% (127/10502)

Publications
 

Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet V, Ahmed-Arab M, Dross C, Dupont M, Cattan D, Smaoui N, Dodé C, Pêcheux C, Nédelec B, Medaxian J, Rozenbaum M, Rosner I, Delpech M, Grateau G, Demaille J, Weissenbach J, Touitou I. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PubMed PMID: 9668175.

 

Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999 Apr;64(4):949-62. PubMed PMID: 10090880; PubMed Central PMCID: PMC1377819.

 

Topaloglu R, Ozaltin F, Yilmaz E, Ozen S, Balci B, Besbas N, Bakkaloglu A. E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis. 2005 May;64(5):750-2. Epub 2004 Sep 30. PubMed PMID: 15458961; PubMed Central PMCID: PMC1755471.

 

show discussion

Discussion

Should we keep a reference to this work?

Tchernitchko DO, Gérard-Blanluet M, Legendre M, Cazeneuve C, Grateau G, Amselem S. Intrafamilial segregation analysis of the p.E148Q MEFV allele in familial Mediterranean fever. Ann Rheum Dis. 2006 Sep;65(9):1154-7. Epub 2006 Jan 26. PubMed PMID: 16439437; PubMed Central PMCID: PMC1798299.

The authors examined 21 patients and 48 unaffected relatives belonging to 18 independent families with FMF. Segregation analysis of the p.E148Q allele was compatible with a Mendelian autosomal recessive transmission of the disease phenotype in only three families. In 15 of 18 families, segregation was partly or completely defective.

Marek-Yagel D, Bar-Joseph I, Pras E, Berkun Y. Is E148Q a benign polymorphism or a disease-causing mutation? J Rheumatol. 2009 Oct;36(10):2372. PubMed PMID: 19820229.

No significant association found in a large meta-analysis.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
58 766 163 2639 0.2138 1.226

 

Genomes
 

 

GS18555 - var-GS18555-1100-36-ASM
het G @ chr16:3244627

 

GS18558 - var-GS18558-1100-36-ASM
het G @ chr16:3244627

 

GS18940 - var-GS18940-1100-36-ASM
het G @ chr16:3244627

 

GS18947 - var-GS18947-1100-36-ASM
het G @ chr16:3244627

 

Other external references
 

    dbSNP
  • rs3743930
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.852 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = –2
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in