ClinVar

Description

Across a selection of available literature, the MEFV c.1772T>C (p.Ile591Thr) missense variant has been identified in a total of 17 patients with familial Mediterranean fever (FMF), including in a compound heterozygous state in five patients and in a heterozygous state in twelve patients (Touitou 2001; Aldea et al. 2002; Tchernitchko et al. 2005; Fisher et al. 2005; Cañete et al. 2007; Ustek et al. 2008; Cornelius et al. 2011; Ait-Idir et al. 2011; Ceylan et al. 2012; Hernández-Rodríguez et al. 2016). Additionally, Aldea et al. (2002) reported the p.Ile591Thr variant in one affected individual in a compound heterozygous state with another known pathogenic variant. However, two siblings who also carried both of the identified variants were asymptomatic, suggesting that the p.Ile591Thr variant may not be disease-causing. This variant was found in six of 1310 control chromosomes (Aldea et al. 2002; Cañete et al. 2007; Ustek et al. 2008; Ait-Idir et al. 2011) and is reported at a frequency of 0.02336 in the Toscani in Italia population of the 1000 Genomes Project. Additionally, twenty three homozygotes are present in the Genome Aggregation Database. Based on the combined evidence, this variant does not appear to be disease-causing in the same manner as known pathogenic FMF variants, but some of the studies suggest that this variant may be a risk allele, modifier or mild allele that displays low penetrance. The p.Ile591Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial Mediterranean fever. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.