ClinPred outperformed 21 other in-silico tools in predicting damaging variants of TRP channels with an AUC of 0.90, and combined with paralogue annotation and structural analysis, suggested the pathogenicity of 80 TRPM4 variants of unknown significance.
In silico tools, particularly ClinPred, combined with structural analysis, identified 80 TRPM4 variants of unknown clinical significance as likely pathogenic, potentially aiding the diagnosis of inherited arrhythmias.
Effect estimate: AUC 0.90
BACKGROUND: TRPM4 is a calcium-activated channel that selectively permeates monovalent cations. Genetic variants of the channel in cardiomyocytes are associated with various heart disorders, such as progressive familial heart block and Brugada syndrome. About97% of all known TRPM4 missense variants are classified as variants of unknown clinical significance (VUSs). The very large number of VUSs is a serious problem in diagnostics and treatment of inherited heart diseases. METHODS AND RESULTS: We collected 233 benign or pathogenic missense variants in the superfamily of TRP channels from databases ClinVar, Humsavar and Ensembl Variation to compare performance of 22 algorithms that predict damaging variants. We found that ClinPred is the best-performing tool for TRP channels. We also used the paralogue annotation method to identify disease variants across the TRP family. In the set of 565 VUSs of hTRPM4, ClinPred predicted pathogenicity of 299 variants. Among these, 12 variants are also categorized as LP/P variants in at least one paralogue of hTRPM4. We further used the cryo-EM structure of hTRPM4 to find scores of contact pairs between parental (wild type) residues of VUSs for which ClinPred predicts a high probability of pathogenicity of variants for both contact partners. We propose that 68 respective missense VUSs are also likely pathogenic variants. CONCLUSIONS: ClinPred outperformed other in-silico tools in predicting damaging variants of TRP channels. ClinPred, the paralogue annotation method, and analysis of residue contacts the hTRPM4 cryo-EM structure collectively suggest pathogenicity of 80 TRPM4 VUSs.
Tarnovskaya et al. (Fri,) conducted a other in TRPM4 variants of unknown clinical significance. ClinPred algorithm vs. 21 other variant interpretation tools was evaluated on Accuracy and AUC for predicting pathogenic variants (AUC 0.90). ClinPred outperformed 21 other in-silico tools in predicting damaging variants of TRP channels with an AUC of 0.90, and combined with paralogue annotation and structural analysis, suggested the pathogenicity of 80 TRPM4 variants of unknown significance.