BACKGROUND The Cystic Fibrosis database includes amongst the 1893 gene mutations and polymorphisms a lot of missense mutations, the disease status of which still remains unproven. In populations with high rates of CFTR mutation heterogeneity, molecular diagnosis is difficult often causing counseling difficulties especially in cases of rare and/or novel mutations. METHODS Approaches to counseling in cases of novel variants. RESULTS Thirty-seven novel variants (4 synonymous, 24 missense, 2 frameshift and 10 intronic substitutions) were identified and evaluated with the help of in silico tools. CONCLUSIONS In a diagnostic environment the answers have to be given within a specific timeframe, the in silico tools in combination with the phenotype offer some help but their diagnostic value is limited and cannot be used in isolation for the determination of the severity of the mutation.