ClinVar Miner

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

dbSNP: rs28930068
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000414086 SCV000342944 pathogenic not provided 2016-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000414086 SCV000490450 pathogenic not provided 2022-01-03 criteria provided, single submitter clinical testing Published functional studies demonstrate membrane depolarization (Jurkat-Rott et al., 2009); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10639629, 7847370, 16767662, 30090141, 11555352, 17418573, 19225109, 28857175, 31068157, 31567646, 33184660, 29572832, 11591859, 33042247, 9066893, 7650604, 19118277)
Invitae RCV000627793 SCV000653633 pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1239 of the CACNA1S protein (p.Arg1239His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypokalemic periodic paralysis (PMID: 7847370, 10639629, 11555352, 17418573, 21841462, 25213595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17623). 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%. Experimental studies have shown that this missense change affects CACNA1S function (PMID: 19225109). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000019190 SCV000803550 pathogenic Hypokalemic periodic paralysis, type 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).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000019190 SCV001976700 pathogenic Hypokalemic periodic paralysis, type 1 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PM5, PP3, PP5
3billion RCV000019190 SCV002012153 pathogenic Hypokalemic periodic paralysis, type 1 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as de novo and observed in at least two similarly affected unrelated individuals (PMID:34008892, 26252573, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:29572832, 28857175, 19225109, PS3). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg1239Gly) has been reported as pathogenic (VCV000017624.7, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3Cnet: 0.869, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA RCV000019190 SCV002061170 pathogenic Hypokalemic periodic paralysis, type 1 2022-01-05 criteria provided, single submitter clinical testing The c.3716G>A;p.(Arg1239His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17623; OMIM: 114208.0001; PMID: 34008892; 11555352; 21841462; 25213595; 20301512PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 19225109; 29572832) - PS3_moderate. This variant is not present in population databases (rs28930068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 17624 - c.3715C>G;p.(Arg1239Gly) - ) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 34008892) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 7847370; 17418573; 11555352) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000414086 SCV002562964 pathogenic not provided 2021-10-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450645 SCV004177653 pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000019190 SCV004177654 pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000414086 SCV004229525 pathogenic not provided 2023-03-28 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with HOKPP and segregates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools predict that this variant is damaging.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003992159 SCV004810028 uncertain significance Congenital myopathy 18 2024-04-04 criteria provided, single submitter clinical testing
OMIM RCV000019190 SCV000039478 pathogenic Hypokalemic periodic paralysis, type 1 1995-02-01 no assertion criteria provided literature only
GeneReviews RCV000019190 SCV000040412 not provided Hypokalemic periodic paralysis, type 1 no assertion provided literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences RCV000019190 SCV002600038 pathogenic Hypokalemic periodic paralysis, type 1 2022-04-12 no assertion criteria provided research

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