This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: 7987325, 7847370, 11034874, 15098604) and other diverse phenotypes, including muscle atrophy and myopathy (PMID: 17587224, 28972032). Incomplete penetrance in female family members has been reported for this variant (PMID: 7847370, 15098604). Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1583G>A (p.Arg528His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant, a change from a strongly positive arginine residue to a weakly positive histidine residue, occurs within the S4 transmembrane segment of the channel pore, which appears to participate in voltage sensing. Based on the available evidence, the c.1583G>A (p.Arg528His) variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)
Germline
Classification
Help
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.
(14)
Help
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
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)
Variation ID: 17625 Accession: VCV000017625.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q32.1 1: 201077915 (GRCh38) [ NCBI UCSC ] 1: 201047043 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000069.3:c.1583G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000060.2:p.Arg528His missense NC_000001.11:g.201077915C>T NC_000001.10:g.201047043C>T NG_009816.2:g.39652G>A Q13698:p.Arg528His - Protein change
- R528H
- Other names
- -
- Canonical SPDI
- NC_000001.11:201077914:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| CACNA1S | No evidence available | No evidence available |
GRCh38 GRCh37 |
2683 | 2711 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2019 | RCV000019192.39 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 11, 2023 | RCV000414449.34 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000627794.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 7, 2021 | RCV002504808.2 | |
|
CACNA1S-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 25, 2024 | RCV004751219.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
HYPOKALEMIC PERIODIC PARALYSIS, TYPE 1
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001445907.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: … (more)
This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: 7987325, 7847370, 11034874, 15098604) and other diverse phenotypes, including muscle atrophy and myopathy (PMID: 17587224, 28972032). Incomplete penetrance in female family members has been reported for this variant (PMID: 7847370, 15098604). Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1583G>A (p.Arg528His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant, a change from a strongly positive arginine residue to a weakly positive histidine residue, occurs within the S4 transmembrane segment of the channel pore, which appears to participate in voltage sensing. Based on the available evidence, the c.1583G>A (p.Arg528His) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypokalemic periodic paralysis, type 1
Thyrotoxic periodic paralysis, susceptibility to, 1 Malignant hyperthermia, susceptibility to, 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002814883.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491250.5
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995); Published functional studies demonstrate that this variant results in … (more)
Reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995); Published functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20541469, 22253645, 17587224, 11328898, 28325641, 28857175, 28972032, 31567646, 31447099, 33584831, 7847370, 9512357, 23187123, 19225109, 11034874, 7987325, 19825159, 25983995, 31068157, 31380823, 19118277, 8605978, 11591859, 11808349, 15098604, 9066893, 7650604, 25088161, 32528171) (less)
|
|
|
Pathogenic
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544352.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
CACNA1S: PS4, PM2, PM5, PS3:Moderate, PP1, PP3
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440200.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
|
|
|
Pathogenic
(Dec 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713928.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_moderate, PM6, PM2, PP3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000612594.4
First in ClinVar: Jan 09, 2017 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant segregates with … (more)
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant segregates with HOKPP in multiple families, including several with observed incomplete penetrance. This variant has been confirmed to occur de novo in multiple individuals with clinical features of HOKPP associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to disrupt CACNA1S calcium channel function, causing potassium-dependent paradoxical membrane depolarization in response to hypokalemia (PMID: 8605978, 19225109, 23187123). (less)
|
|
|
Pathogenic
(Apr 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018031.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000653632.9
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 528 of the CACNA1S protein (p.Arg528His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the CACNA1S protein (p.Arg528His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 7847370, 7987325, 9066893, 11034874, 11808349, 15726306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17625). 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: 8605978, 9512357, 9852570, 23187123). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 22, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hypokalemic periodic paralysis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000747828.1
First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
Comment:
The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by … (more)
The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2. (less)
Clinical Features:
Generalized morning stiffness (present)
Age: 30-39 years
Sex: male
Ethnicity/Population group: Hindu/Gujarati
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to the human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Apr 12, 2022)
|
no assertion criteria provided
Method: research
|
Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
germline
|
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002600036.1
First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022 |
|
|
|
Pathogenic
(Mar 01, 1999)
|
no assertion criteria provided
Method: literature only
|
HYPOKALEMIC PERIODIC PARALYSIS, TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039480.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
By sequencing of cDNA of the CACNL1A3 gene in 2 patients with hypokalemic periodic paralysis (HOKPP1; 170400), Jurkat-Rott et al. (1994) demonstrated a heterozygous G-to-A … (more)
By sequencing of cDNA of the CACNL1A3 gene in 2 patients with hypokalemic periodic paralysis (HOKPP1; 170400), Jurkat-Rott et al. (1994) demonstrated a heterozygous G-to-A transition in nucleotide 1583 predicting a substitution of histidine for arginine-528 (R528H). The mutation affected the outermost positive charge in the transmembrane segment IIS4 that was considered to participate in voltage sensing. By restriction fragment analysis, the mutation was detected in the affected members of 9 out of 25 hypokalemic periodic paralysis families. An altered excitation-contraction coupling may explain the occurrence of muscle weakness. Elbaz et al. (1995), who found the arg528-to-his mutation in 8 of 16 families of Caucasian origin, demonstrated that incomplete penetrance is a distinctive feature of this mutation. Boerman et al. (1995) found this mutation in 55 affected members of a Dutch kindred. In skeletal muscle biopsies from 3 patients with the R528H mutation, Tricarico et al. (1999) found reduced conductance through ATP-sensitive sarcolemmal potassium channels. The potassium channels showed reduced open probability and several subconductance states. Tricarico et al. (1999) hypothesized that the abnormal potassium channel conductance resulted from altered calcium homeostasis. The findings provided an explanation for some of the clinical features of the disorder, including hypokalemia and insulin-induced paralysis. (less)
|
|
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Pathogenic
(Jul 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CACNA1S-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005352415.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The CACNA1S c.1583G>A variant is predicted to result in the amino acid substitution p.Arg528His. This variant has been frequently reported in patients with hypokalemic periodic … (more)
The CACNA1S c.1583G>A variant is predicted to result in the amino acid substitution p.Arg528His. This variant has been frequently reported in patients with hypokalemic periodic paralysis (Jurkat-Rott et al. 1994. PubMed ID: 7987325; Jurkat-Rott et al. 2009. PubMed ID: 19225109; Luo et al. 2019. PubMed ID: 31068157). A mouse model of the p.Arg528His variant displays many of the human clinical features of hypokalemic periodic paralysis (Wu et al. 2012. PubMed ID: 23187123). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hypokalemic periodic paralysis, type 1
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040407.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995); Published functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20541469, 22253645, 17587224, 11328898, 28325641, 28857175, 28972032, 31567646, 31447099, 33584831, 7847370, 9512357, 23187123, 19225109, 11034874, 7987325, 19825159, 25983995, 31068157, 31380823, 19118277, 8605978, 11591859, 11808349, 15098604, 9066893, 7650604, 25088161, 32528171)
Comment:
CACNA1S: PS4, PM2, PM5, PS3:Moderate, PP1, PP3
Comment:
This variant was identified as compound heterozygous.
Comment:
PS3, PS4_moderate, PM6, PM2, PP3
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant segregates with HOKPP in multiple families, including several with observed incomplete penetrance. This variant has been confirmed to occur de novo in multiple individuals with clinical features of HOKPP associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to disrupt CACNA1S calcium channel function, causing potassium-dependent paradoxical membrane depolarization in response to hypokalemia (PMID: 8605978, 19225109, 23187123).
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the CACNA1S protein (p.Arg528His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 7847370, 7987325, 9066893, 11034874, 11808349, 15726306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17625). 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: 8605978, 9512357, 9852570, 23187123). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.
Comment:
The CACNA1S c.1583G>A variant is predicted to result in the amino acid substitution p.Arg528His. This variant has been frequently reported in patients with hypokalemic periodic paralysis (Jurkat-Rott et al. 1994. PubMed ID: 7987325; Jurkat-Rott et al. 2009. PubMed ID: 19225109; Luo et al. 2019. PubMed ID: 31068157). A mouse model of the p.Arg528His variant displays many of the human clinical features of hypokalemic periodic paralysis (Wu et al. 2012. PubMed ID: 23187123). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic.
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. |
Comment:
This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: 7987325, 7847370, 11034874, 15098604) and other diverse phenotypes, including muscle atrophy and myopathy (PMID: 17587224, 28972032). Incomplete penetrance in female family members has been reported for this variant (PMID: 7847370, 15098604). Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1583G>A (p.Arg528His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant, a change from a strongly positive arginine residue to a weakly positive histidine residue, occurs within the S4 transmembrane segment of the channel pore, which appears to participate in voltage sensing. Based on the available evidence, the c.1583G>A (p.Arg528His) variant is classified as Pathogenic.
Comment:
Reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995); Published functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20541469, 22253645, 17587224, 11328898, 28325641, 28857175, 28972032, 31567646, 31447099, 33584831, 7847370, 9512357, 23187123, 19225109, 11034874, 7987325, 19825159, 25983995, 31068157, 31380823, 19118277, 8605978, 11591859, 11808349, 15098604, 9066893, 7650604, 25088161, 32528171)
Comment:
CACNA1S: PS4, PM2, PM5, PS3:Moderate, PP1, PP3
Comment:
This variant was identified as compound heterozygous.
Comment:
PS3, PS4_moderate, PM6, PM2, PP3
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant segregates with HOKPP in multiple families, including several with observed incomplete penetrance. This variant has been confirmed to occur de novo in multiple individuals with clinical features of HOKPP associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to disrupt CACNA1S calcium channel function, causing potassium-dependent paradoxical membrane depolarization in response to hypokalemia (PMID: 8605978, 19225109, 23187123).
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the CACNA1S protein (p.Arg528His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 7847370, 7987325, 9066893, 11034874, 11808349, 15726306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17625). 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: 8605978, 9512357, 9852570, 23187123). For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.
Comment:
The CACNA1S c.1583G>A variant is predicted to result in the amino acid substitution p.Arg528His. This variant has been frequently reported in patients with hypokalemic periodic paralysis (Jurkat-Rott et al. 1994. PubMed ID: 7987325; Jurkat-Rott et al. 2009. PubMed ID: 19225109; Luo et al. 2019. PubMed ID: 31068157). A mouse model of the p.Arg528His variant displays many of the human clinical features of hypokalemic periodic paralysis (Wu et al. 2012. PubMed ID: 23187123). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Electromyographic Features in a Chinese Cohort With Hereditary Skeletal Muscle Channelopathies. | Sun J | Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society | 2020 | PMID: 31567646 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Hypokalemic periodic paralysis due to CACNA1S gene mutation. | Alhasan KA | Neurosciences (Riyadh, Saudi Arabia) | 2019 | PMID: 31380823 |
| Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing. | Luo S | BMC neurology | 2019 | PMID: 31068157 |
| Diverse phenotype of hypokalaemic periodic paralysis within a family. | Chalissery AJ | Practical neurology | 2018 | PMID: 28972032 |
| Hypokalemic Periodic Paralysis. | Adam MP | - | 2018 | PMID: 20301512 |
| A calcium channel mutant mouse model of hypokalemic periodic paralysis. | Wu F | The Journal of clinical investigation | 2012 | PMID: 23187123 |
| 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 |
| Progressive muscle atrophy with hypokalemic periodic paralysis and calcium channel mutation. | Meyer T | Muscle & nerve | 2008 | PMID: 17587224 |
| The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. | Kim JB | Journal of Korean medical science | 2007 | PMID: 18162704 |
| Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. | Wang Q | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15726306 |
| Skeletal muscle dihydropyridine-sensitive calcium channel (CACNA1S) gene mutations in chinese patients with hypokalemic periodic paralysis. | Lin SH | The American journal of the medical sciences | 2005 | PMID: 15711422 |
| A family of hypokalemic periodic paralysis with CACNA1S gene mutation showing incomplete penetrance in women. | Kawamura S | Internal medicine (Tokyo, Japan) | 2004 | PMID: 15098604 |
| [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 |
| 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 |
| Identification of mutations including de novo mutations in Korean patients with hypokalaemic periodic paralysis. | Kim SH | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2001 | PMID: 11328898 |
| Clinical-molecular study of a family with essential tremor, late onset seizures and periodic paralysis. | Domínguez-Morán JA | Seizure | 2000 | PMID: 11034874 |
| Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. | Tricarico D | The Journal of clinical investigation | 1999 | PMID: 10074484 |
| Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H. | Morrill JA | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1998 | PMID: 9852570 |
| Calcium currents and transients of native and heterologously expressed mutant skeletal muscle DHP receptor alpha1 subunits (R528H). | Jurkat-Rott K | FEBS letters | 1998 | PMID: 9512357 |
| Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families. | Sillén A | American journal of medical genetics | 1997 | PMID: 9066893 |
| Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells. | Lapie P | FEBS letters | 1996 | PMID: 8605978 |
| Mutation in DHP receptor alpha 1 subunit (CACLN1A3) gene in a Dutch family with hypokalaemic periodic paralysis. | Boerman RH | Journal of medical genetics | 1995 | PMID: 7897626 |
| 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 |
| Skeletal muscle DHP receptor mutations alter calcium currents in human hypokalaemic periodic paralysis myotubes. | Sipos I | The Journal of physiology | 1995 | PMID: 7650604 |
| A calcium channel mutation causing hypokalemic periodic paralysis. | Jurkat-Rott K | Human molecular genetics | 1994 | PMID: 7987325 |
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Text-mined citations for rs80338777 ...
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Record last updated Oct 20, 2024
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