ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His) (rs28930068)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414086 SCV000342944 pathogenic not provided 2016-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000414086 SCV000490450 pathogenic not provided 2017-03-20 criteria provided, single submitter clinical testing The R1239H pathogenic variant in the CACNA1S gene has been reported previously in multiple individuals with hypokalemic periodic paralysis (Elbaz et al., 1995; Houinato et al., 2007; Kusumi et al., 2001). Functional studies showed that myofibers with the R1239H variant had a non-selective cation leak that sensitized the myofibers to reduced serum potassium, which resulted in membrane depolarization (Jurkat-Rott et al., 2009). The R1239H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1239H variant is a conservative amino acid substitution and occurs at a position that is conserved across species. Additionally, missense variants at the same residue (R1239G) and in a nearby residue (R1242G) have been reported in the Human Gene Mutation Database in association with CACNA1S-related disorders (Stenson et al., 2014). Therefore, we interpret R1239H as a pathogenic variant.
GeneReviews RCV000019190 SCV000040412 pathologic Hypokalemic periodic paralysis 1 2009-04-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000627793 SCV000653633 pathogenic Hypokalemic periodic paralysis 1; Malignant hyperthermia susceptibility 5 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1239 of the CACNA1S protein (p.Arg1239His). 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 in many individuals affected with hypokalemic periodic paralysis (PMID: 10639629, 11555352, 21841462, 25213595). It has also been reported to segregate with hypokalemic periodic paralysis in multiple families (PMID: 7847370, 17418573). ClinVar contains an entry for this variant (Variation ID: 17623). Experimental studies have shown that this missense change alters the permeability of the CACNA1S ion channel (PMID: 19225109). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019190 SCV000039478 pathogenic Hypokalemic periodic paralysis 1 1995-02-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000019190 SCV000803550 pathogenic Hypokalemic periodic paralysis 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Periodic paralysis hypokalemic 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:8004673). PS2 => De novo (paternity and maternity confirmed). Only paternity confirmed, but since article has been published in 1994, we can assume no need to confirm maternity (PMID:8004673). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:8004673,18162704,17418573,19118277). PS3 => Well-established functional studies show a deleterious effect (PMID:28857175,29572832).

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