ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)

dbSNP: rs28930069
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518061 SCV000612604 pathogenic not provided 2014-06-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000693727 SCV000821608 pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2024-05-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1239 of the CACNA1S protein (p.Arg1239Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 8004673, 15716625, 18162704, 18229654). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17624). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1S protein function with a positive predictive value of 80%. This variant disrupts the p.Arg1239 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 17418573, 19225109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000518061 SCV001780892 pathogenic not provided 2021-07-20 criteria provided, single submitter clinical testing Recurrent variant associated with hypokalemic periodic paralysis (Matthews et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 15221887, 26252573, 15711422, 19779499, 18229654, 15716625, 19118277, 20301512, 11353725, 8004673, 21891927)
Genome-Nilou Lab RCV003450646 SCV004177655 pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000019191 SCV004177656 pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000019191 SCV000039479 pathogenic Hypokalemic periodic paralysis, type 1 1994-06-17 no assertion criteria provided literature only
GeneReviews RCV000019191 SCV000040411 not provided Hypokalemic periodic paralysis, type 1 no assertion provided literature only

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