MEFV
Genetic findings for MEFV in Familial Mediterranean Fever
Variants (5)
| Variant | Type | Frequency | Significance |
|---|---|---|---|
| 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. |
Clinical implications
M694V (c.2080A>G, p.Met694Val)
M694V homozygotes require early aggressive treatment. Higher risk of colchicine resistance. Close monitoring for amyloidosis essential.
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).
V726A (c.2177T>C, p.Val726Ala)
Usually milder disease when heterozygous. Complex alleles with E148Q can cause severe phenotype including amyloidosis.
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.
M694I (c.2082G>A/C, p.Met694Ile)
Severe phenotype when homozygous, especially regarding amyloidosis risk.
Related molecules
Inflammasome sensor protein (mutated in FMF) — Gain-of-function mutations
Related hypotheses
High carrier frequency of MEFV mutations reflects heterozygote advantage against intracellular pathogens, particularly Yersinia pestis
65FMF heterozygotes can manifest clinical disease through a pseudo-dominant or dose-dependent mechanism involving gene modifiers and environmental triggers
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