ClinVar Genomic variation as it relates to human health
NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)
Variation ID: 17624 Accession: VCV000017624.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201053539 (GRCh38) [ NCBI UCSC ] 1: 201022667 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 28, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000069.3:c.3715C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000060.2:p.Arg1239Gly missense NC_000001.11:g.201053539G>C NC_000001.10:g.201022667G>C NG_009816.2:g.64028C>G Q13698:p.Arg1239Gly - Protein change
- R1239G
- Other names
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- Canonical SPDI
- NC_000001.11:201053538:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CACNA1S | No evidence available | No evidence available |
GRCh38 GRCh37 |
2201 | 2232 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Apr 11, 2023 | RCV000019191.33 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2021 | RCV000518061.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2021 | RCV000693727.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450646.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 02, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000612604.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jul 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001780892.1
First in ClinVar: Aug 12, 2021 Last updated: Aug 12, 2021 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Malignant hyperthermia, susceptibility to, 5
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004177655.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004177656.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 1
Malignant hyperthermia, susceptibility to, 5
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000821608.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1239 amino acid residue in CACNA1S. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 17624). 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 1239 of the CACNA1S protein (p.Arg1239Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. (less)
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Pathogenic
(Jun 17, 1994)
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no assertion criteria provided
Method: literature only
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HYPOKALEMIC PERIODIC PARALYSIS, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039479.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In affected family members with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous C-to-G transversion at a position analogous to basepair … (more)
In affected family members with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous C-to-G transversion at a position analogous to basepair 3715 in rabbit cDNA. The change from CGT to GGT predicted a substitution of an arginine residue with a glycine residue at a position corresponding to amino acid 1239 in the rabbit DHP receptor (Tanabe et al., 1987). (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hypokalemic periodic paralysis, type 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040411.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hypokalemic Periodic Paralysis. | Adam MP | - | 2018 | PMID: 20301512 |
K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. | Jurkat-Rott K | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19225109 |
Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. | Matthews E | Neurology | 2009 | PMID: 19118277 |
The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. | Kim JB | Journal of Korean medical science | 2007 | PMID: 18162704 |
Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family. | Houinato D | Neuromuscular disorders : NMD | 2007 | PMID: 17418573 |
Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. | Sternberg D | Brain : a journal of neurology | 2001 | PMID: 11353725 |
Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-type Ca2+ channel expressed in Xenopus laevis oocytes. | Morrill JA | The Journal of physiology | 1999 | PMID: 10523403 |
Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis. | Fouad G | Neuromuscular disorders : NMD | 1997 | PMID: 9132138 |
Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. | Elbaz A | American journal of human genetics | 1995 | PMID: 7847370 |
Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. | Ptácek LJ | Cell | 1994 | PMID: 8004673 |
Primary structure of the receptor for calcium channel blockers from skeletal muscle. | Tanabe T | Nature | 1987 | PMID: 3037387 |
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Text-mined citations for rs28930069 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.