Submissions for variant NM_000069.3(CACNA1S):c.5104C>T (p.Arg1702Ter)

dbSNP: rs550371466

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454946	SCV000538557	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The ACMG has recommended that ONLY known pathogenic variants for MH be reported as incidental findings. LOF not a known disease mechanism for MH.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814679	SCV000955098	pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1702*) in the CACNA1S gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1S are known to be pathogenic (PMID: 26247046, 28012042). This variant is present in population databases (rs550371466, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive CACNA1S-related conditions (PMID: 29792937; Invitae). ClinVar contains an entry for this variant (Variation ID: 402469). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001096066	SCV001252254	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000782224	SCV001789398	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported previously in an individual undergoing genetic testing for a myopathy or muscular dystrophy phenotype, although no specifics about this individual were described (Zenagui et al., 2018) This variant is associated with the following publications: (PMID: 29792937)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454946	SCV003801332	uncertain significance	not specified	2023-01-26	criteria provided, single submitter	clinical testing	Variant summary: CACNA1S c.5104C>T (p.Arg1702X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.2e-05 in 251228 control chromosomes. The observed variant frequency is approximately 73 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1S causing autosomal dominant Hypokalemic Periodic Paralysis phenotype (1.3e-06), strongly suggesting that the variant is benign. c.5104C>T has been reported in the literature as a compound heterozygous genotype with other loss of function (LOF) variants in the CACNA1S gene in at-least two individuals affected with features of Myopathies and muscular dystrophies (Zenagui_2018, captured in Juntas_2021), and/or neuromuscular disease with neonatal respiratory distress (example, Franois-Heude_2021). These data indicate that the variant may be associated with disease. However, to our knowledge, this variant has not been reported in settings of dominantly inherited Hypokalemic Periodic Paralysis or other CACNA1S-related disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, due to ambiguity related to the exact inheritance pattern (dominant or recessive), molecular mechanism of disease and the clinical validity of the reported association(s), the variant was classified as uncertain significance.
Gharavi Laboratory, Columbia University	RCV000782224	SCV000920711	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004751528	SCV005367665	uncertain significance	CACNA1S-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The CACNA1S c.5104C>T variant is predicted to result in premature protein termination (p.Arg1702*). This variant has been reported in an individual with myopathy, but no family or functional data were provided to help assess the pathogenicity of this variant (Zenagui et al 2018. PubMed ID: 29792937). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.