ClinVar

Description

Variant summary: MEFV c.1760-4G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 250940 control chromosomes, predominantly at a frequency of 0.017 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. This frequency is not significantly higher (somewhat lower) than expected for a pathogenic variant in MEFV causing Familial Mediterranean Fever (0.0012 vs 0.022), allowing no conclusion about variant significance, however, considering also the several homozygotes, the variant might still represent a benign polymorphism. To our knowledge, no occurrence of c.1760-4G>A in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. The variant, c.1760-4G>A, has been reported by the International Study Group for Systemic Autoinflammatory Diseases (INSAID), with an experts consensus as "likely benign" (Van Gijn_2018). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and predominantly as benign/likely benign (n=3). Based on the evidence outlined above, due to the absence of any actionable evidence supporting an association with disease, the variant was classified as benign.