MEFV
7 variant(s) documented across Adult-Onset Still's Disease, Familial Mediterranean Fever, Schnitzler Syndrome
Found across diseases
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| Multiple variants including common FMF-associated mutations (E148Q, M694V, etc.) | germline | 15-63% carry variants depending on population (53% in Korean, 63% in Japanese, 15-28% in Caucasian) | Elevated MEFV variant frequency suggests genetic overlap between AOSD and hereditary periodic fever syndromes, supporting the autoinflammatory disease continuum | Familial Mediterranean Fever (Homozygous in >80%); Schnitzler Syndrome (Emerging (2024-2025)) |
| M694V (c.2080A>G, p.Met694Val) | germline | ~40% of disease alleles (most common) | The most common and most severe FMF mutation. Located in exon 10 (B30.2/SPRY domain). Homozygosity associated with earliest onset, highest attack frequency, most arthritis, and greatest risk of AA amyloidosis. | — |
| M680I (c.2040G>A/C, p.Met680Ile) | germline | ~11% of disease alleles | Third most common FMF mutation. Located in exon 10. Homozygosity or compound heterozygosity with M694V associated with severe disease. M680I/M694V combination produces severe phenotype. | — |
| V726A (c.2177T>C, p.Val726Ala) | germline | ~14% of disease alleles | Second most common FMF mutation. Located in exon 10. Heterozygosity generally associated with milder phenotype. However, V726A-E148Q complex allele can be severe. | — |
| E148Q (c.442G>C, p.Glu148Gln) | germline | ~3% of disease alleles (controversial pathogenicity) | Located in exon 2. Highly controversial — debated whether pathogenic variant or benign polymorphism. Extremely high frequency in general population. When part of a complex allele with V726A, significantly increases disease severity. | — |
| M694I (c.2082G>A/C, p.Met694Ile) | germline | ~3% of disease alleles | Located in exon 10. Fifth founder mutation. Homozygosity associated with severe disease. M694I/M694I genotype identified as a specific risk factor for AA amyloidosis in Algerian patients. | — |
| c.2084A>G and p.(Glu148Gln) | germline | Emerging (2024-2025 reports) | MEFV encodes pyrin, an inflammasome inhibitor. Variants could lower the threshold for inflammasome activation. | Familial Mediterranean Fever (Causative (homozygous/compound het)) |
Clinical implications
Multiple variants including common FMF-associated mutations (E148Q, M694V, etc.)
MEFV variants may lower the threshold for inflammasome activation; partial response to colchicine reported in patients with MEFV mutations
Testing: Sanger sequencing, Next-generation sequencing, Targeted gene panel
M694V (c.2080A>G, p.Met694Val)
M694V homozygotes require early aggressive treatment. Higher risk of colchicine resistance. Close monitoring for amyloidosis essential.
Testing: targeted mutation analysis, Sanger sequencing, next-generation sequencing panels
M680I (c.2040G>A/C, p.Met680Ile)
Severe disease when homozygous or compound with M694V. More frequent in patients with skin eruptions (erysipelas-like erythema).
Testing: targeted mutation analysis, Sanger sequencing, next-generation sequencing panels
V726A (c.2177T>C, p.Val726Ala)
Usually milder disease when heterozygous. Complex alleles with E148Q can cause severe phenotype including amyloidosis.
Testing: targeted mutation analysis, Sanger sequencing, next-generation sequencing panels
E148Q (c.442G>C, p.Glu148Gln)
Clinical significance uncertain when found alone. Should not be used as sole basis for FMF diagnosis. Complex alleles containing E148Q merit attention.
Testing: targeted mutation analysis, Sanger sequencing, next-generation sequencing panels
M694I (c.2082G>A/C, p.Met694Ile)
Severe phenotype when homozygous, especially regarding amyloidosis risk.
Testing: targeted mutation analysis, Sanger sequencing, next-generation sequencing panels
c.2084A>G and p.(Glu148Gln)
Potential genetic modifier. Significance uncertain.
Testing: Sanger sequencing, NGS panels
Related hypotheses
Genetic susceptibility via HLA polymorphisms and autoinflammatory gene variants predisposes to AOSD
45