L-Type Calcium Channel: Predicting Pathogenic/Likely Pathogenic Status for Variants of Uncertain Clinical Significance.

Svetlana I Tarnovskaya,Anna A Kostareva,Boris S Zhorov

doi:10.3390/membranes11080599

Abstract

(1) Background: Defects in gene CACNA1C, which encodes the pore-forming subunit of the human Cav1.2 channel (hCav1.2), are associated with cardiac disorders such as atrial fibrillation, long QT syndrome, conduction disorders, cardiomyopathies, and congenital heart defects. Clinical manifestations are known only for 12% of CACNA1C missense variants, which are listed in public databases. Bioinformatics approaches can be used to predict the pathogenic/likely pathogenic status for variants of uncertain clinical significance. Choosing a bioinformatics tool and pathogenicity threshold that are optimal for specific protein families increases the reliability of such predictions. (2) Methods and Results: We used databases ClinVar, Humsavar, gnomAD, and Ensembl to compose a dataset of pathogenic/likely pathogenic and benign variants of hCav1.2 and its 20 paralogues: voltage-gated sodium and calcium channels. We further tested the performance of sixteen in silico tools in predicting pathogenic variants. ClinPred demonstrated the best performance, followed by REVEL and MCap. In the subset of 309 uncharacterized variants of hCav1.2, ClinPred predicted the pathogenicity for 188 variants. Among these, 36 variants were also categorized as pathogenic/likely pathogenic in at least one paralogue of hCav1.2. (3) Conclusions: The bioinformatics tool ClinPred and the paralogue annotation method consensually predicted the pathogenic/likely pathogenic status for 36 uncharacterized variants of hCav1.2. An analogous approach can be used to classify missense variants of other calcium channels and novel variants of hCav1.2.

Highlights

L-type Cav1.2 calcium channels are expressed in various excitable cells including cardiomyocytes [1]
For the 21 channels listed in Table 1, we collected a total of 7164 missense variants from the databases gnomAD, ClinVar, Uniprot, and Humsavar (Table S1)
No pathogenic/likely pathogenic (P/LP) variants were found for channels hCav3.3 and hNav2.1 (Table 1)

Summary

Introduction

L-type Cav1.2 calcium channels are expressed in various excitable cells including cardiomyocytes [1]. Defects in gene CACNA1C, which encodes the pore-forming α1 subunit of the hCav1.2 channel, underlie cardiac disorders such as atrial fibrillation, long QT syndrome, conduction disorders, cardiomyopathies, and congenital heart defects [2]. With the advent of whole-exome sequencing data, public databases are rapidly replenished with new gene variants. The guideline of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) recommends the employment of computational tools to predict damaging variants [3]. Numerous computational tools, which are based on different principles, have been developed to predict the pathogenicity and tolerance of genetic variants [4]. The ACMG/AMP guideline recommends the employment of multiple software programs for variants’ interpretation because individual programs and underlying algorithms have their own strengths and weaknesses. The choice of bioinformatics tools is critical for reliable variant interpretation

Methods

Results

Discussion

Conclusion