Abstract: Background: Long QT syndrome (LQTS) is the most common, autosomal dominant, sudden death predisposing cardiac channelopathy.Whole exome sequencing (WES) followed by a strategic variant filtration approach may elucidate novel LQTSsusceptibility genes.Objective: N/A Methods: A LQTS family with multiple sudden deaths was referred for genetic evaluation.The index case was a 21-yearold male who died suddenly but had a pre-mortem ECG with marked QT prolongation.His mother also showed QT prolongation.Genomic DNA isolated from the mother and her deceased son was analyzed by WES.Following WES, variants were filtered based on autosomal dominant inheritance using Ingenuity Variant Analysis (IVA) software.Only non-synonymous variants with a minor allele frequency <0.00005 in public exome database were considered.Electrophysiological studies were performed on the variant with highest probability of pathogenicity.Results: Following WES, a CALR frame-shift variant (R376fs/10) was considered a probable LQTS mutation.No radical CALR variants reside in ExAC's 60,000+ exomes.The mutation was confirmed in the decedent's PET-derived DNA.CALR-encoded calreticulin (CRT) is a Ca 2+ binding chaperone of the endoplasmic reticulum and is linked with altered L-type calcium (LTCC) ion channel activity.Wild-type (WT)-CALR reduced Cav1.2peak current density by 43.1%.In contrast, CALR-R376fs/10 mutation reversed this Cav1.2inhibition and caused a net gain-of-function of Cav1.2 channel current compared with CALR-WT co-expression (64.2% increase).Confocal microscopy studies showed a significantly reduced colocalization of Cav1.2 and CALR-R376fs/10 compared to CALR-WT.Furthermore, CALR-R376fs/10 increased the cell surface membrane expression of Cav1.2 by 84%.We injected the mRNA of CALR-WT or CALR-R376fs/10 into the zebrafish embryos and performed optical mapping with Di-8-ANEPPS at 72hpf.Action potential at 80% repolarization (APD80) was significantly prolonged in the ventricle of CALR-R376fs/10 injected zebrafish heart compared to CALR-WT. Conclusion:Mutations in CALR-encoded calreticulin may be a rare cause of autosomal dominant LQTS precipitated in part by an accentuation of the LTCC, thereby potentially mimicking CACNA1C-mediated LQTS.