ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His) (rs80338777)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414449 SCV000491250 pathogenic not provided 2018-03-20 criteria provided, single submitter clinical testing The R528H variant in the CACNA1S gene has been reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995). Functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012). The R528H variant is not observed in large population cohorts (Lek et al., 2016). The R528H variant is a conservative amino acid substitution, which occurs at a position within an S4 transmembrane segment of the protein. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Other missense variants at the same residue (R528G, R528C) have been reported in the Human Gene Mutation Database in individuals with hypokalemic periodic paralysis (Stenson et al., 2014; Wang et al., 2005; Yang et al., 2014). We interpret R528H as a pathogenic variant.
Athena Diagnostics Inc RCV000414449 SCV000612594 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000627794 SCV000653632 pathogenic Hypokalemic periodic paralysis 1; Malignant hyperthermia, susceptibility to, 5 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 528 of the CACNA1S protein (p.Arg528His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypokalemic periodic paralysis in many affected families (PMID: 7847370, 7987325, 11034874, 11808349). Incomplete penetrance has been reported for this variant (PMID: 9066893, 15726306). ClinVar contains an entry for this variant (Variation ID: 17625). Experimental studies have shown that this missense change alters the electrophysiological properties of the CACNA1S channel and a mouse model carrying this variant recapitulates the hypokalemic periodic paralysis phenotype (PMID: 8605978, 9512357, 9852570, 23187123). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000019192 SCV001440200 pathogenic Hypokalemic periodic paralysis 1 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000019192 SCV001445907 pathogenic Hypokalemic periodic paralysis 1 2019-08-01 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: 7987325, 7847370, 11034874, 15098604) and other diverse phenotypes, including muscle atrophy and myopathy (PMID: 17587224, 28972032). Incomplete penetrance in female family members has been reported for this variant (PMID: 7847370, 15098604). Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1583G>A (p.Arg528His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant, a change from a strongly positive arginine residue to a weakly positive histidine residue, occurs within the S4 transmembrane segment of the channel pore, which appears to participate in voltage sensing. Based on the available evidence, the c.1583G>A (p.Arg528His) variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000414449 SCV001713928 pathogenic not provided 2020-12-30 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM6, PM2, PP3
OMIM RCV000019192 SCV000039480 pathogenic Hypokalemic periodic paralysis 1 1999-03-01 no assertion criteria provided literature only
GeneReviews RCV000019192 SCV000040407 pathologic Hypokalemic periodic paralysis 1 2009-04-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000019192 SCV000747828 pathogenic Hypokalemic periodic paralysis 1 2017-02-22 no assertion criteria provided clinical testing The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.

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