Figure 4.

A web-based application makes paralogue annotation easily accessible for genes causing inherited arrhythmia syndromes. A web-based application is available at http://cardiodb.org/Paralogue_Annotation/. Users enter the position of a novel variant using complementary DNA or protein coordinates: in this example a substitution has been found in RYR2, affecting glycine residue 357.¹ This residue maps to RYR1 residue 341, and two cDNA variants at that location (c.1021G>A and c.1021G>C) that each cause substitution of Arg for Gly at that position have been reported to cause malignant hyperthermia. Users should check the alignment quality—here the mapping quality is high: the surrounding region is highly homologous, the reference amino acid is the same in both proteins, and the alignment has a high consensus score.² Pubmed links give access to the reports relating to the paralogue mutation(s), ³ allowing users to assess the quality of evidence for pathogenicity. Here functional characterisation has been performed on this variant in the highlighted publication, adding confidence that the variant is disease causing and the residue is intolerant of variation in both RYR1 and its paralogue RYR2.