In particular, the algorithms for predicting the functional effect of missense variants estimate the probability that a mutation is disease-associated or functionally deleterious.
Currently, it is very difficult to decide if a CFTR mutation is disease-causing or rather a neutral variant and if a specific gene is modifying the CF phenotype or not.
Analysis of a knock-in mouse for one of the reported mutations (N641Y) showed homozygous mice to be significantly more susceptible to seizures [ Singh et al, 2009], supporting the hypothesis that this mutation is disease-causing.
In addition, the dis-equilibrium could possibly be explained by a reduced number of homozygous cats, which supports that the p.A31P cMyBP-C mutation was disease-causing and resulted in an increased mortality even in young cats.
Thus, the segregation of the mutations in the family is consistent with the mutations being disease causing (Fig. 2A).
The homozygous in vitro model was not stimulated by the KATP channel agonist diazoxide, a finding which is consistent with these mutations being disease causing.
However, the likelihood that de novo mutations are disease-causing can only be determined when such genetic changes are both bioinformatically and functionally tested (Davies et al., 2012; Shanks et al., 2013 b ).
However, R229Q inherited with a pathogenic mutation is not disease causing in all cases and at the age of 68, individual I.1 remains well.
The trustworthiness of annotations can be rated by users as well as the likelihood of a mutation to be disease causing (Fig. 1).
