ClinVar Genomic variation as it relates to human health

The MEFV c.250G>A (p.Glu84Lys) variant has been reported in at least six studies in which it is found in at least 23 individuals with familial Mediterranean fever (FMF) including in five in a compound heterozygous state, in four in a complex compound heterozygous state, and in fourteen in a heterozygous state, six of whom presented with an atypical form of FMF. The p.Glu84Lys variant was also detected in four individuals who carried the same two additional variants with unknown phase (Tomiyama et al. 2008; Kishida et al. 2014; Migita et al. 2014; Yoshioka et al. 2014; Kitade et al. 2015; Nonaka et al. 2015). The p.Glu84Lys variant is described as a low-penetrance variant based on the carrier rate in the Japanese general population (Migita et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.014423 in the Japanese in Tokyo, Japan population of the 1000 Genomes Project. Despite the high frequency in public databases, based on the collective evidence, the p.Glu84Lys variant is classified as pathogenic for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The MEFV c.250G>A; p.Glu84Lys variant (rs150819742) is reported in the literature in several individuals with familial Mediterranean fever (Kernan 2018, Kitade 2015, Migita 2014, Tomiyama 2008). Some of these individuals were reported as compound heterozygous but not with a known pathogenic MEFV variant. This variant is found in the general population with an overall allele frequency of 0.01% (27/248852 alleles) and increased frequency of 0.1% in East Asians (Genome Aggregation Database). The glutamate at codon 84 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kernan KF et al. Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. Genes Immun. 2018 Jul 6. Kitade T et al. Usefulness of Small Intestinal Endoscopy in a Case of Adult-onset Familial Mediterranean Fever Associated with Jejunoileitis. Intern Med. 2015;54(11):1343-7. Migita K et al. Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients. Medicine (Baltimore). 2014 May;93(3):158-64. Tomiyama N et al. MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol. 2008 Jan-Feb;26(1):13-7.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 84 of the MEFV protein (p.Glu84Lys). This variant is present in population databases (rs150819742, gnomAD 0.1%). This missense change has been observed in individual(s) with familial Mediterranean fever (PMID: 24797171, 27473114). ClinVar contains an entry for this variant (Variation ID: 632250). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect MEFV function (PMID: 33733382). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.