RE-EVALUATION OF MEFV GENE VARIANTS: UTILITY OF A GENE SPECIFIC THRESHOLD IN REDUCING THE NUMBER OF VARIANTS OF UNKNOWN SIGNIFICANCE

Abstract

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still in large part classified as variant of uncertain significance (VOUS), or with classification unresolved, posing significant challenges in the clinical diagnosis of Familial Mediterranean Fever (FMF). REVEL is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification we extracted the REVEL score for all missense variants reported at the locus specific database INFEVERS, and analyzed its correlation with expert-based classification and localization in the MEFV-encoded pyrin protein functional domains. The data set of 216 missense variants was divided in four classification categories (BENIGN, VOUS, PATHOGENIC and UNRESOLVED). MEFV variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated. We observed a non-random distribution of pathogenic variants along the functional domains of the pyrin protein. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases (INSAID). Sensitivity, specificity, and accuracy were calculated for different cutoff values of REVEL scores and a gene-specific threshold was computed with confidence boundary limits. A REVEL score of 0.298 was the best performing cut-off to reclassify 96 MEFV gene variants previously of uncertain significance or unsolved thus reducing their proportion from 61.6% to 17.6%. In conclusion, the combination of available expert information with highly sensitive predictor tools yields to more accurate interpretation of clinical consequences of MEFV gene variants. This approach should bring to a better genetic counseling and patient management. Author summaryWe aimed to refine MEFV gene variants classification using the metapredictor REVEL. We demonstrate that a gene-specific threshold is effective for accurate variants classification. Using this threshold, we reduced significantly the proportion of MEFV variants with an ambiguous classification. The proposed classification could represent a useful resource for variant interpretation in the context of FMF diagnosis.