The CACNA1S gene encodes the α1s subunit of the dihydropyridine receptor (DHPR), a voltage-gated calcium channel and voltage sensor for Ca2+ release in skeletal muscle. Variants in the CACNA1S gene have been linked to the pharmacogenetic disorder known as malignant hyperthermia susceptibility (MHS) and hypokalemic periodic paralysis (hypoPP). Two variants in CACNA1S are verified by the European Malignant Hyperthermia Group (EMHG) to be associated with MHS [1]. Although the occurrence of MHS during anesthesia is relatively rare, the genetic prevalence of MHS-causative mutations is estimated to be between 1 in 400 [2] to 1 in 2000–3000 [3]. The American College of Medical Genetics (ACMG) “Guidelines for Reporting Incidental Findings in Clinical Exome and Genome Sequencing” includes “known pathogenic” and “likely pathogenic” variants in CACNA1S related to MHS in its list of genetic variants to report as incidental findings [4, 5]. In addition, 9 CACNA1S variants are linked to hypoPP [6]. Finally, several CACNA1S variants and polymorphisms are proposed to be associated with thyrotoxic periodic paralysis (TPP) [7], hyperCKemia [8] and statin-associated myopathy [9]. Thus, the CACNA1S gene is associated with an eclectic array of muscle disorders with clinical manifestations ranging from subclinical myopathies, episodic paralysis, and life-threatening response to anesthesia.