ClinVar Genomic variation as it relates to human health
NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)
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.1582C>T (p.Arg528Cys)
Variation ID: 849085 Accession: VCV000849085.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201077916 (GRCh38) [ NCBI UCSC ] 1: 201047044 (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 15, 2020 Apr 20, 2024 Jun 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000069.3:c.1582C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000060.2:p.Arg528Cys missense NC_000001.11:g.201077916G>A NC_000001.10:g.201047044G>A NG_009816.2:g.39651C>T - Protein change
- R528C
- Other names
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- Canonical SPDI
- NC_000001.11:201077915:G:A
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
2646 | 2676 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2020 | RCV001052970.1 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV002307667.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV002505605.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003455233.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2019 | RCV004017781.1 |
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
Help
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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Likely pathogenic
(Jan 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis 1
Malignant hyperthermia susceptibility type 5
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001217210.1
First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020 |
Comment:
This sequence change replaces arginine with cysteine at codon 528 of the CACNA1S protein (p.Arg528Cys). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with cysteine at codon 528 of the CACNA1S protein (p.Arg528Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338778, ExAC 0.003%). This variant has been observed in individual(s) with hypokalaemic periodic paralysis (PMID: 25430699). It has also been observed to segregate with disease in related individuals. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg528 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 7987325, 11034874, 11808349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Feb 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002817246.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 33088529, 25430699). Other variants resulting in a different missense change at this codon have been reported to be pathogenic, suggesting this arginine residue is critical and its disruption is likely to be disease-causing (PMID: 7847370, 7987325, 11034874, 11808349). Computational tools yielded predictions that this amino acid change may be damaging to the protein. Clinical presentation is noted to be variable and reduced penetrance has been reported for females (PMID: 28972032, 15726306, 18835861, 20301512).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Likely pathogenic
(Jun 15, 2023)
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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: SCV003933484.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Reported as heterozygous in individuals in the published literature with hypokalemic periodic paralysis, and also in two asymptomatic individuals (Rezkalla et al., 2020; Yang et … (more)
Reported as heterozygous in individuals in the published literature with hypokalemic periodic paralysis, and also in two asymptomatic individuals (Rezkalla et al., 2020; Yang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33088529, 25430699) (less)
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Likely 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: SCV004179057.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004179059.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely Pathogenic
(Mar 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848216.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg528Cys variant in CACNA1S has been reported in one individual with hypokalemic periodic paralysis, and segregated with disease in 3 affected male relatives. Two … (more)
The p.Arg528Cys variant in CACNA1S has been reported in one individual with hypokalemic periodic paralysis, and segregated with disease in 3 affected male relatives. Two female relatives who carried the variant were asymptomatic (Yang 2014). Of note, incomplete penetrance of hypokalemic periodic paralysis in female individuals has been previously described (Ke 2013). The p.Arg528Cys variant has been identified in 2/111426 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338778). Computational prediction tools and conservation analysis suggest that the p.Arg528Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a different pathogenic variant at this position (p.Arg528His) has been reported in ClinVar (Variation ID: 17625). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg528Cys variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP1, PP3. (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: SCV002600288.1
First in ClinVar: Nov 19, 2022 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 |
A rare case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis caused by a novel dominant mutation in CACNA1S: features and prognosis after adrenalectomy. | Yang B | BMC urology | 2014 | PMID: 25430699 |
Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. | Ke Q | Muscle & nerve | 2013 | PMID: 23019082 |
[A case of familial hypokalemic periodic paralysis with hyperuricemia during paralytic attack and genetic analysis of the pedigree]. | Katsuno M | Rinsho shinkeigaku = Clinical neurology | 2001 | PMID: 11808349 |
Clinical-molecular study of a family with essential tremor, late onset seizures and periodic paralysis. | Domínguez-Morán JA | Seizure | 2000 | PMID: 11034874 |
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 |
A calcium channel mutation causing hypokalemic periodic paralysis. | Jurkat-Rott K | Human molecular genetics | 1994 | PMID: 7987325 |
Text-mined citations for rs80338778 ...
HelpRecord last updated Apr 20, 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.