ClinVar

Description

Variant summary: MEFV c.436C>T (p.Gln146X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 233434 control chromosomes (ExAC). To our knowledge, no occurrence of c.436C>T in individuals affected with Familial Mediterranean Fever and no experimental evidence demonstrating its impact on protein function have been reported. However, HGMD cites two nonsense variants, p.Tyr471X and p.Tyr688X, downstream of this variant in affected individuals (Notarnicola_2011, Berdeli_2011). In addition, a ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, and considering that nonsense variants in this gene are very rare, the variant was classified as VUS-possibly pathogenic.