MEFV R202Q - GET-Evidence

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Curation:
Currentness:

MEFV R202Q

(MEFV Arg202Gln)


Short summary

This variant may increase susceptibility to Familial Mediterranean Fever.

Variant evidence
Computational 1

Gene associated with disease
PolyPhen2: Benign; score 0.001
SIFT: Tolerated
GVGD:GV 126.59; GD 0.00; Class C0
Variant Effect Predictor (Ensembl ):
SIFT=tolerated(0.31);
PolyPhen=benign(0.001);
Condel=deleterious(0.557)
Mutation Tasting prediction: Polymorphism p value: 0.999546; Protein features (might be) affected.

See Ritis K et al. 2004 (15020340).

Functional -
Case/Control 2

OR=1.7, p-value 0.021 (Fisher Exact)

See Ritis K et al. 2004 (15020340), Giaglis S et al. 2007 (17489852), Villani AC et al. 2009 (19784369), unpublished research (below).

Familial

No familial data.

 
Clinical importance
Severity 1

If this variant has an effect, it is probably only to increase susceptibility to FMF, which would otherwise be 3 points (moderate effect on quality of life).

See unpublished research (below).

Treatability 4

Colchicine treatment alleviates symptoms

See Ritis K et al. 2004 (15020340), Giaglis S et al. 2007 (17489852), unpublished research (below).

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

In (http://journals.tubitak.gov.tr/medical/issues/sag-08-38-3/sag-38-3-4-0802-28.pdf) the authors report the variant not in complete LD with M694V and they found this variant homozygously in 14/41 Turkish FMF cases and in 0/107 controls. In (http://journals.tubitak.gov.tr/medical/issues/sag-09-39-2/sag-39-2-12-0712-5.pdf) this variant was analyzed in Egyptian patients and was found to not be in LD with M694V and to cause the least number of attacks/year compared with other variants and complete responsiveness to Colchicine.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
14 28 0 107 0.0000

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
33 248 83 1038 0.0214 1.664

 

Allele frequency

  • T @ chr16:3304463: 17.8% (1844/10364) in EVS
  • T @ chr16:3244463: 11.1% (14/126) in GET-Evidence
  • Frequency shown in summary reports: 17.8% (1844/10364)

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.

Authors observed that R202Q is found frequently among non-carrier chromosomes in the families as well as in unrelated controls: 20% of chromosomes from unrelated controls (CEPH panel, at least 120 chromosomes), in 9/56 non-carrier chromosomes in the FMF families and 19/123 carrier chromosomes. Thus, they conclude this is a common polymorphism. Assuming hardy-weinberg equilibrium, this would be case+: 1, case-: 60, control+: 3, control-: 86.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
1 60 3 86 0.6463 0.478

 

Ritis K, Giaglis S, Spathari N, Micheli A, Zonios D, Tzoanopoulos D, Deltas CC, Rafail S, Mean R, Papadopoulos V, Tzioufas AG, Moutsopoulos HM, Kartalis G. Non-isotopic RNase cleavage assay for mutation detection in MEFV, the gene responsible for familial Mediterranean fever, in a cohort of Greek patients. Ann Rheum Dis. 2004 Apr;63(4):438-43. PubMed PMID: 15020340; PubMed Central PMCID: PMC1754936.

Four of 26 individuals with Familial Mediterranean Fever were homozygous for this variant, while none of 60 controls were (p-value 0.007). (1) 3yo Armenian female, (2) 4yo Greek female, (3) 12yo Greek female, (4) 14yo Greek male. It was also found as part of a compound heterozygote in (1)12yo Greek female (with M690I and E167D) and (2) a 12yo Greek male (with M694V). The allelic frequency in N. Greece is 0.125. Previous reports have declared this a polymorphism, but the lack of other mutations in the homozygous cases and the favorable response to colchicine cause the authors to consider this pathogenic.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
4 22 0 60 0.0070

 

Giaglis S, Papadopoulos V, Kambas K, Doumas M, Tsironidou V, Rafail S, Kartalis G, Speletas M, Ritis K. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007 May;71(5):458-67. PubMed PMID: 17489852.

This variant was seen homozygously in 14/152 individuals with FMF (12 of whom harbored no additional disease-associated mutation in MEFV), and was seen homozygously in 1/140 healthy controls. The typical symptoms were fever, serositis and monoarthritis in contrast to abdominal pain. Colchicine was reported as causing significant clinical improvement.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
14 138 1 139 0.0008 14.101

 

Villani AC, Lemire M, Louis E, Silverberg MS, Collette C, Fortin G, Nimmo ER, Renaud Y, Brunet S, Libioulle C, Belaiche J, Bitton A, Gaudet D, Cohen A, Langelier D, Rioux JD, Arnott ID, Wild GE, Rutgeerts P, Satsangi J, Vermeire S, Hudson TJ, Franchimont D. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis. PLoS One. 2009 Sep 28;4(9):e7154. PubMed PMID: 19784369; PubMed Central PMCID: PMC2745755.

In a study of SNPs related to ulcerative colitis, this variant was found with an allelic frequency of 0.27 in 591 controls and 0.26 in 228 cases. If these variants are assumed to be in Hardy-Weinberg Equilibrium and these individuals are assumed to not have Familial Mediterranean Fever, this would be 79/646 controls.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Mediterranean Fever
- - 79 646 - -

 

Genomes
 

 

 

 

 

 

 

 

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het T @ chr16:3304463

 

 

 

 

 

 

 

 

 

GS06985 - var-GS06985-1100-36-ASM
het T @ chr16:3244464

 

GS10851 - var-GS10851-1100-36-ASM
hom T @ chr16:3244464

 

GS19648 - var-GS19648-1100-36-ASM
het T @ chr16:3244464

 

GS19649 - var-GS19649-1100-36-ASM
het T @ chr16:3244464

 

GS20502 - var-GS20502-1100-36-ASM
het T @ chr16:3244464

 

Other external references
 

    dbSNP
  • rs224222
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.019 (benign)
    Web search results (81 hits -- see all)
  • Is MEFV Gene Arg202Gln (605 G>A) A Disease-Causing Mutation?
    Sequencing of exon 10 and exon 5 and PCR/RFLP analysis of E148Q and R202Q mutations of exon 2 of the. MEFV gene were performed for all patients ...
    journals.tubitak.gov.tr/medical/.../sag-38-3-4-0802-28.pdf
  • MEFV
    Our data provide evidence that rare missense variants of the MEFV gene are, collectively, ... R202Q: FMS probands and family members with R202Q genotype (n = 49) ...
    www.fibromyalgiatreatment.com/FMS-PlosOne.pdf
  • sag-39-2-12-0712-5:sag-0
    The aim of this study was to find the distribution of MEFV gene ... 5 and PCR/RFLP analysis of E148Q and R202Q mutations of exon 2 of the MEFV gene ...
    journals.tubitak.gov.tr/medical/.../sag-39-2-12-0712-5.pdf
  • FMF 2005
    The marenostrin/pyrin-encoding gene (MEFV), mapped to the short arm of ... at codon 605 (R202Q) probably represents a common polymorphism of MEFV, since it has been ...
    niams.nih.gov/News_and_Events/Meetings_and_Events/...?ID=217
  • The west side story: MEFV haplotype in Spanish FMF patients ...
    We have analyzed intragenic MEFV SNPs in Spanish and Chueta ... The structure of LD in MEFV can be used to define a set of three tag SNPs; R202Q, plus one of any other SNP ...
    www.upf.edu/bioevo/2004BioEvo/BE2004-Aldea-HumMut.pdf
  • FMF 2005
    Complete MEFV sequencing was performed in 144 Italians with FMF ... with R202Q in heterozygosis and 6/144 (4,2%) patients with R202Q in associations with other MEFV mutations. ...
    niams.nih.gov/News_And_Events/Meetings_and_Events/...?ID=223
  • Rioux, JD (John D)
    Rioux, JD (John D) :: CARD15 genetic variation in a Quebec population: prevalence, ... A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV ...
    lib.bioinfo.pl/auid:9454
  • Familial Mediterranean Fever Gene as a Possible Modifier of ...
    The mutational analysis of the patient revealed a compound heterozygous E148Q/R202Q mutation in exon 2 of MEFV gene, which is a causative gene for familial ...
    content.karger.com/produktedb/produkte.asp?doi=158578
  • G.I.D. - Groupe Inter-académique pour le Développement
    Over 80 mutations have been identified in the gene (MEFV) responsible for the disease. ... as a possible cause of the disease (R202Q ; promotor mutations, 5' mutations) ...
    g-i-d.org/spip.php?article62
  • Non-founder mutations in the MEFV gene establish this gene as ...
    The first line depicts the MEFV. gene exon positions.The second line depicts the sequence ... bears a non-conservative amino acid polymorphism (R202Q) ...
    hmg.oxfordjournals.org/cgi/reprint/7/8/1317.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

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