The histidine-rich calcium-binding protein, which is encoded by the HRC gene in humans, plays a crucial role in cardiac arrhythmia development, especially in cases involving calcium-handling dysfunction [1]. This sarcoplasmic reticulum (SR) binding protein in the heart muscle cells, acts as an intracellular Ca2+ buffer and tightly regulates Ca2+ binding and release [2]. In silico studies can help to identify effective single nucleotide polymorphisms (SNPs) in the structure and stability of HRC protein and to predict their relationship with cardiac arrhythmias [3]. In this study, missense SNPs of the HRC gene and their effects on arrhythmia were investigated. At first, all missense SNPs of the HRC gene, which is located on chromosome 17q25.3 monitored. Missense SNPs with a minor allele frequency (MAF)≥ 0.1 were selected in the NCBI-dbSNP database. The effect of each of the selected SNPs based on functional, structural, and stability aspects of the protein were investigated by eleven online software:SIFT, Polyphen-2, Mutation assessor, PROVEAN, I-mutant, iStable, MUpro, SNPs&GO, PhD-SNP, HOPE, PSIPRED, and GOR-IV. Analysis of missense SNPs performed with SIFT, Polyphen-2, and Mutation assessor software showed that rs3745297 (T>G, Ser96Ala), as a transversion mutation, could be a deleterious SNP. The prediction of the effects of this transversion by I-mutant, iStable, MUpro databases, PSIPRED and GOR-IV also showed that the substitution of Serin with Alanine at the residue region 96 may decrease the stability of the protein and change the secondary structure. Since serine 96 of this protein is a critical phosphorylation site for binding to Triadin (TRDN) [4], which is a regulatory protein for releasing Ca2+, Ser96Ala substitution may prevent this binding and thus disrupt the HRC- TRDN pathway in individuals with mutant allele G. Based on this, the rs3745297 can be suggested as a molecular marker for further research in cardiac arrhythmia.
