ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)

gnomAD frequency: 0.00002  dbSNP: rs80338778
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001052970 SCV001217210 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2020-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 528 of the CACNA1S protein (p.Arg528Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338778, ExAC 0.003%). This variant has been observed in individual(s) with hypokalaemic periodic paralysis (PMID: 25430699). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg528 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 7987325, 11034874, 11808349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics RCV002505605 SCV002817246 likely pathogenic not provided 2021-02-09 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 33088529, 25430699). Other variants resulting in a different missense change at this codon have been reported to be pathogenic, suggesting this arginine residue is critical and its disruption is likely to be disease-causing (PMID: 7847370, 7987325, 11034874, 11808349). Computational tools yielded predictions that this amino acid change may be damaging to the protein. Clinical presentation is noted to be variable and reduced penetrance has been reported for females (PMID: 28972032, 15726306, 18835861, 20301512).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
GeneDx RCV002505605 SCV003933484 likely pathogenic not provided 2023-06-15 criteria provided, single submitter clinical testing Reported as heterozygous in individuals in the published literature with hypokalemic periodic paralysis, and also in two asymptomatic individuals (Rezkalla et al., 2020; Yang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33088529, 25430699)
Genome-Nilou Lab RCV003455233 SCV004179057 likely pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002307667 SCV004179059 likely pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017781 SCV004848216 likely pathogenic Hypokalemic periodic paralysis 2019-03-20 criteria provided, single submitter clinical testing The p.Arg528Cys variant in CACNA1S has been reported in one individual with hypokalemic periodic paralysis, and segregated with disease in 3 affected male relatives. Two female relatives who carried the variant were asymptomatic (Yang 2014). Of note, incomplete penetrance of hypokalemic periodic paralysis in female individuals has been previously described (Ke 2013). The p.Arg528Cys variant has been identified in 2/111426 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338778). Computational prediction tools and conservation analysis suggest that the p.Arg528Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a different pathogenic variant at this position (p.Arg528His) has been reported in ClinVar (Variation ID: 17625). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg528Cys variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP1, PP3.
GeneReviews RCV002307667 SCV002600288 not provided Hypokalemic periodic paralysis, type 1 no assertion provided literature only

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