ClinVar Genomic variation as it relates to human health
NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)
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.
Pathogenic(11); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)
Variation ID: 17623 Accession: VCV000017623.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201053538 (GRCh38) [ NCBI UCSC ] 1: 201022666 (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 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000069.3:c.3716G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000060.2:p.Arg1239His missense NC_000001.11:g.201053538C>T NC_000001.10:g.201022666C>T NG_009816.2:g.64029G>A Q13698:p.Arg1239His - Protein change
- R1239H
- Other names
- NM_000069.2(CACNA1S):c.3716G>A(p.Arg1239His)
- Canonical SPDI
- NC_000001.11:201053537:C:T
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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
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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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000019190.45 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 28, 2023 | RCV000414086.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV000627793.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992159.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450645.1 |
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
Help
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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Pathogenic
(Jun 17, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000342944.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976700.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PM5, PP3, PP5
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Pathogenic
(Jan 03, 2022)
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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: SCV000490450.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Mar 28, 2023)
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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: SCV004229525.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Hypokalemic periodic paralysis, type 1
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803550.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061170.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
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; … (more)
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. (less)
Number of individuals with the variant: 2
Sex: male
Geographic origin: Brazil
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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: SCV004177653.1
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: SCV004177654.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV002012153.2
First in ClinVar: Nov 11, 2021 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability, mild (present) , Periodic hypokalemic paresis (present) , Global developmental delay … (more)
Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability, mild (present) , Periodic hypokalemic paresis (present) , Global developmental delay (present) (less)
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Pathogenic
(Dec 06, 2023)
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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: SCV000653633.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Oct 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002562964.10
First in ClinVar: Aug 23, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Congenital myopathy 18
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810028.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Feb 01, 1995)
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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: SCV000039478.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In patients with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous G-to-A transition at a position analogous to basepair 3716 in … (more)
In patients with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous G-to-A transition at a position analogous to basepair 3716 in rabbit cDNA (Tanabe et al., 1987). The change from CGT to CAT predicted substitution of an arginine residue by a histidine at a position corresponding to amino acid 1239 in the rabbit DHP receptor. This arginine is completely conserved among genes encoding DHP receptors from rabbit, carp, ray, and human skeletal muscle. Elbaz et al. (1995) demonstrated a de novo heterozygous arg1239-to-his mutation. (less)
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Pathogenic
(Apr 12, 2022)
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no assertion criteria provided
Method: research
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Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
germline
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Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002600038.1
First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022 |
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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: SCV000040412.3
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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Short-Communication: Variable Expression of Clinical Symptoms and an Unexpected Finding of Vacuolar Myopathy Related to a Pathogenic Variant in the CACNA1S Gene in a Previous Case Report. | Benítez-Alonso EO | Cureus | 2022 | PMID: 35509735 |
Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes. | Brugnoni R | Neurogenetics | 2022 | PMID: 34608571 |
Vacuolar Myopathy Associated to CACNA1S Mutation as a Rare Cause of Late-Onset Limb-Girdle Myopathy: A Case Report. | López-Hernández JC | Cureus | 2021 | PMID: 34804722 |
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
Morphological Alterations of the Sarcotubular System in Permanent Myopathy of Hereditary Hypokalemic Periodic Paralysis with a Mutation in the CACNA1S Gene. | Nagasaka T | Journal of neuropathology and experimental neurology | 2020 | PMID: 33184660 |
Primary Hypokalemic Periodic Paralysis: Long-term Management and Complications in a Child. | Sharawat IK | Journal of pediatric neurosciences | 2020 | PMID: 33042247 |
Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing. | Luo S | BMC neurology | 2019 | PMID: 31068157 |
Phenotypical Variation with Same Genetic Mutation in Familial Hypokalemic Periodic Paralysis. | Kumar S | Journal of pediatric neurosciences | 2018 | PMID: 30090141 |
When muscle Ca(2+) channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis. | Allard B | The Journal of physiology | 2018 | PMID: 29572832 |
Hypokalemic Periodic Paralysis. | Adam MP | - | 2018 | PMID: 20301512 |
Elevated resting H(+) current in the R1239H type 1 hypokalaemic periodic paralysis mutated Ca(2+) channel. | Fuster C | The Journal of physiology | 2017 | PMID: 28857175 |
Mutation analysis of CACNA1S and SCN4A in patients with hypokalemic periodic paralysis. | Wang XY | Molecular medicine reports | 2015 | PMID: 26252573 |
Muscle edema of the lower limb determined by MRI in Asian hypokalaemic periodic paralysis patients. | Jia BX | Neurological research | 2015 | PMID: 25213595 |
Genotype and phenotype analysis of patients with sporadic periodic paralysis. | Sung CC | The American journal of the medical sciences | 2012 | PMID: 21841462 |
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 |
Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK. | Davies NP | Neurology | 2001 | PMID: 11591859 |
Muscle weakness in a Japanese family of Arg1239His mutation hypokalemic periodic paralysis. | Kusumi M | Psychiatry and clinical neurosciences | 2001 | PMID: 11555352 |
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 |
Muscle fiber conduction velocity in arg1239his mutation in hypokalemic periodic paralysis. | Links TP | Muscle & nerve | 2000 | PMID: 10639629 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1S | - | - | - | - |
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Text-mined citations for rs28930068 ...
HelpRecord last updated Apr 15, 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.