rs28940580 — MEFV M680I

MEFV M680I — A Severity-Hotspot Founder Mutation at Pyrin's Regulatory Core

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease, driven by gain-of-function variants in MEFV that destabilize pyrin's normally tight control over the inflammasome. Pyrin¹¹ Pyrin
a 781-amino acid protein expressed in neutrophils, monocytes, and dendritic cells that assembles the pyrin inflammasome and controls caspase-1-mediated IL-1β release; named for the Greek word for fever operates as a conditional alarm sensor — active only when genuine pathogen-derived toxins disable the regulatory Rho GTPase pathway. FMF mutations lower this threshold, triggering unprovoked IL-1β storms that manifest as self-limiting 12–72 hour attacks of fever and serositis. M680I is one of five founder mutations²² founder mutations
mutations that arose in a common ancestral population and persisted as carrier groups migrated across the Mediterranean and Middle East; the five account for ~74% of FMF chromosomes in Armenians, Arabs, Jews, and Turks that collectively define the FMF mutation spectrum.

M680I (c.2040G>C on the coding strand, p.Met680Ile) sits in exon 10 at codon 680 — one of two severity hotspots in pyrin's B30.2 regulatory domain. Touitou (2001)³³ Touitou (2001) described codons 680 and 694 as the "mutational hot-spots" of the gene and found that genotypes combining two mutations within these codons are consistently associated with severe phenotypes. ClinVar classifies all three c.2040G> nucleotide variants (G>C, G>A, G>T) as Pathogenic or Pathogenic/Likely pathogenic across independent submissions, with no conflicts.

The Mechanism

Met680 lies within the B30.2 (SPRY) domain⁴⁴ B30.2 (SPRY) domain
the C-terminal regulatory domain of pyrin that senses effectors of the RhoA GTPase signaling axis; when the Rho pathway is disrupted by bacterial toxins, B30.2 detects this and licenses inflammasome assembly of pyrin, at a position closely adjacent to the codon 694 hotspot occupied by M694V and M694I. In the resting state, the regulatory kinases PKN1 and PKN2 phosphorylate pyrin at S208 and S242, and the 14-3-3 proteins bind to hold the inflammasome inactive. Substituting the bulky, flexible methionine at position 680 with the branched-chain isoleucine alters the local conformation of the B30.2 domain, disrupting the PKN1/14-3-3 regulatory contact. The result is partial constitutive inflammasome activation: caspase-1 cleaves pro-IL-1β and pro-IL-18 without the microbial trigger normally required, producing episodes of sterile inflammation in serosal and joint tissues.

The severity of the M680I dysfunction — while unambiguously pathogenic — is intermediate. Being at codon 680 rather than 694 produces a slightly different disruption geometry than M694V, explaining why M680I homozygotes may have a moderately different colchicine responsiveness profile than M694V homozygotes. However, when M680I is combined with M694V on the opposite chromosome, the compound heterozygous phenotype approaches the severity of M694V homozygosity.

The Evidence

M680I is the second most commonly identified MEFV disease allele in large FMF cohorts. In the largest published pediatric FMF registry — Öztürk et al. 2022⁵⁵ Öztürk et al. 2022, n=3,454 patients — M680I accounted for 11.3% of all disease alleles, compared to 55.3% for M694V and 7.6% for V726A. Exon 10 mutation carriers as a group had earlier disease onset (4.6 vs. 5.6 years for exon 2 carriers) and more frequent attacks. Population genetics meta-analysis (Papadopoulos et al. 2008⁶⁶ Papadopoulos et al. 2008, cumulative dataset) confirmed M680I at 11.4% of disease alleles across Mediterranean populations, with the mutation enriched primarily in Armenian and Turkish founder groups.

The severity framework for M680I is grounded in the codon-hotspot principle. Touitou (2001) established that genotypes combining two mutations at codons 680 and/or 694 reliably produce severe disease. A systematic review by Gangemi et al. 2018⁷⁷ Gangemi et al. 2018 — covering over 280 MEFV variants — confirmed that M680I homozygotes and M680I/M694 compound heterozygotes have severe disease presentations, though precise quantitative severity scores for isolated M680I homozygosity are less thoroughly characterized in the literature than for M694V, reflecting that homozygous M680I patients are outnumbered by M694V homozygotes in most published cohorts (e.g., 3 vs. 7 homozygotes in one Egyptian registry of 426 patients, Al-Haggar et al. 2014⁸⁸ Al-Haggar et al. 2014).

Compound heterozygosity with M694V is the most clinically critical M680I configuration. Barut et al. 2018⁹⁹ Barut et al. 2018 documented that pediatric amyloidosis cases arose in M694V homozygotes and M694V/M680I compound heterozygotes — placing M680I in the same high-risk amyloidosis tier as M694V when combined with a second high-severity allele. Caglayan et al. 2010¹⁰¹⁰ Caglayan et al. 2010 found M680I in 14.5% of disease alleles in their compound heterozygous FMF cohort; overall colchicine effectiveness was 83% regardless of mutation type, suggesting M680I compound heterozygotes are generally colchicine-responsive, though a subset requiring IL-1 inhibitors is enriched for M694V/M680I genotypes.

Practical Implications

For heterozygous carriers of M680I without clinical FMF symptoms, no colchicine treatment is warranted. FMF is autosomal recessive; a single M680I allele is generally insufficient for full-expression disease, though subclinical inflammatory marker elevation has been documented in obligate heterozygotes across the MEFV hotspot mutations. The clinically urgent scenario is the undiagnosed compound heterozygote: a person carrying M680I on one chromosome and M694V (or another pathogenic allele) on the other may develop clinically significant FMF requiring colchicine — and will be missed by single-site testing.

For confirmed FMF patients (homozygous M680I or compound heterozygous), colchicine at 1.0–2.0 mg/day is the standard prophylactic therapy. The target is complete attack suppression AND normalization of inter-attack serum amyloid A (SAA) — the latter is critical because sustained subclinical elevation of SAA drives the reactive AA amyloidosis that historically caused renal failure and death in inadequately treated FMF. Colchicine is highly effective in the majority of M680I patients; the subset with persistent attacks on ≥2 mg/day should be evaluated for IL-1 inhibitor therapy (anakinra or canakinumab).

Periodic urinalysis for proteinuria (every 6 months) is recommended as an early screen for renal AA amyloidosis, per EULAR FMF management guidelines, in all confirmed pathogenic MEFV genotypes.

Interactions

M680I's most clinically important interaction is compound heterozygosity with M694V (rs61752717). The M694V/M680I compound genotype elevates disease severity above what either allele alone might predict in heterozygosity, approaching the severe tier associated with M694V homozygosity. These patients tend to have higher colchicine requirements and are among those most likely to require IL-1 inhibitor escalation.

M680I can also form a compound genotype with V726A (rs28940579). The V726A/M680I combination appears in Arab and Turkish cohorts and produces a moderate phenotype — more active than V726A homozygosity but less severe than M694V-containing compound genotypes. Compared with M694V/M680I, V726A/M680I disease course is more manageable on standard colchicine doses.

For any M680I heterozygote presenting with FMF-like symptoms, a comprehensive MEFV panel covering all common exon 10 mutations (M694V, M694I, V726A) and E148Q (rs3743930) is the necessary next step before concluding that M680I heterozygosity alone explains the phenotype.