Submissions for variant NM_000069.3(CACNA1S):c.1493G>T (p.Arg498Leu)

dbSNP: rs150590855

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656816	SCV000329190	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	Reported previously in an individual with malignant hyperthermia susceptibility (PMID: 25735680); Reported previously in an individual with Takotsubo cardiomyopathy that underwent whole exome sequencing; however, CACNA1S was only reported as a candidate gene and other potentially pathogenic variants were also reported in this individual (PMID: 25132214); Reported previously as a variant of uncertain significance in a patient with recurrent exertional rhabdomyolysis and possible malignant hyperthermia susceptibility; this patient also had a pathogenic variant in a different gene related to a separate diagnosis (PMID: 30094188); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32054689, 25132214, 25735680, 30094188)
Illumina Laboratory Services, Illumina	RCV000277233	SCV000353115	benign	Hypokalemic periodic paralysis, type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Athena Diagnostics	RCV000326557	SCV000612591	benign	not specified	2024-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560360	SCV000653639	likely benign	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519032	SCV003651888	uncertain significance	Inborn genetic diseases	2022-09-03	criteria provided, single submitter	clinical testing	The c.1493G>T (p.R498L) alteration is located in exon 11 (coding exon 11) of the CACNA1S gene. This alteration results from a G to T substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.06% (168/282898) total alleles studied. The highest observed frequency was 0.1% (127/129198) of European (non-Finnish) alleles. This alteration was reported to be heterozygous in an individual with malignant hyperthermia susceptibility with positive in vitro contracture tests (Gillies, 2015). This amino acid position is highly conserved in available vertebrate species. The p.R498L alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000656816	SCV004125283	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	CACNA1S: PP3
Revvity Omics, Revvity	RCV000656816	SCV004234916	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000415659	SCV005426067	likely benign	Malignant hyperthermia, susceptibility to, 5	2024-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000326557	SCV005887576	likely benign	not specified	2025-01-23	criteria provided, single submitter	clinical testing	Variant summary: CACNA1S c.1493G>T (p.Arg498Leu) results in a non-conservative amino acid change located in the voltage-dependent channel domain (IPR027359) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00096 in 1461834 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CACNA1S causing Congenital myopathy 18-AR phenotype (0.0011). c.1493G>T has been reported in the literature in individuals affected with Takotsubo cardiomyopathy, malignant hyperthermia, and early onset small-fiber neuropathy (e.g., Gillies_2015, Goodloe_2014, Misra_2024, Sambuughin_2018). These reports do not provide unequivocal conclusions about association of the variant with Congenital myopathy 18-AR. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25735680, 25132214, 39000354, 30094188). ClinVar contains an entry for this variant (Variation ID: 279727). Based on the evidence outlined above, the variant was classified as likely benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415659	SCV000493715	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2015-09-26	no assertion criteria provided	clinical testing