ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000414449 SCV000612594 pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,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.
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.
GeneReviews RCV000019192 SCV000040407 pathologic Hypokalemic periodic paralysis 1 2009-04-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000627794 SCV000653632 pathogenic Hypokalemic periodic paralysis 1; Malignant hyperthermia susceptibility 5 2018-12-17 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.
OMIM RCV000019192 SCV000039480 pathogenic Hypokalemic periodic paralysis 1 1999-03-01 no assertion criteria provided literature only

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