Using SIFT and PolyPhen to Predict Loss-of-Function and Gain-of-Function Mutations

TLDR: Although SIFT and PolyPhen may be useful in prioritizing changes that are likely to cause a loss of protein function, their low specificity means that their predictions should be interpreted with caution and further evidence to support/refute pathogenicity should be sought before reporting novel missense changes.

Abstract: Context: The interpretation of novel missense variants is a challenge with increasing numbers of such variants being identified and a responsibility to report the findings in the context of all available scientific evidence. Various in silico bioinformatic tools have been developed that predict the likely pathogenicity of missense variants; however, their utility within the diagnostic setting requires further investigation. Aim: The aim of our study was to test the predictive value of two of these tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), in a set of 141 missense variants (131 pathogenic, 8 benign) identified in the ABCC8, GCK, and KCNJ11 genes. Methods: Sixty-six of the mutations caused a gain of protein function, while 67 were loss-of-function mutations. The evolutionary conservation at each residue was also investigated using multiple sequence alignments from the UCSC genome browser. Results: The sensitivity of SIFT and PolyPhen was reasonably high (69% and...