ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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.