ClinVar

Description

Variant summary: MEFV c.124C>T (p.Arg42Trp) results in a non-conservative amino acid change located in the DAPIN domain (also called pyrin domain (PYD), IPR004020) which is a protein-protein interaction domain involved in inflammasome assembly (Vajjhala_2014). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 282866 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.004, including 1 homozygote in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.004 vs 0.022), allowing no conclusion about variant significance. c.124C>T has been reported in the literature in individuals affected with Familial Mediterranean Fever (FMF), however without strong evidence for pathogenicity (e.g. Moradian_2017). Therefore these data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence on protein function, demonstrating an increased protein stability, possibly decreased auto-inhibition, but also a decreased protein-protein interaction (with ASC) that is important for the inflammasome assembly; the authors of this study hypothesized that the overall effects of the variant might contribute to FMF by facilitating activation of the pyrin inflammasome (Vajjhala_2014). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, four classifying the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.