CACNA1S

protein-coding

calcium voltage-gated channel subunit alpha1 S, the group of Calcium voltage-gated channel alpha1 subunits

Gene summary

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

Previous symbols:

HOKPP
MHS5
CACNL1A3

MANE transcript

NM_000069.3

Inheritance

AR, AD, SD

ClinVar variants

P:163U:1521B:1003

Top phenotype

Malignant hyperthermia, susceptibility to, 5; Thyrotoxic period paralysis, susceptibility 1; Hypokalemic periodic paralysis, type 1

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr1:201,039,512-201,112,451

External References & Databases

Ensembl (ENSG00000081248)

Transcript & Mutation Effects

hg38 • Region Span ~72.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019952

Submitter: Genomics England PanelApp

hypokalemic periodic paralysis, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0042979

Submitter: Genomics England PanelApp

malignant hyperthermia, susceptibility to, 5MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011163

Submitter: ClinGen

*CACNA1S* was first reported in relation to autosomal dominant malignant hyperthermia in 1997 (Monnier et al., PMID:9199552) and assigned the name “Malignant Hyperthermia susceptibility 5 (OMIM:601887). This condition is a muscle disorder in which an episode is triggered by exposure to volatile anesthetic agents or depolarizing muscle relaxants (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane) either alone or in conjunction with a depolarizing muscle relaxant, leading to muscle rigidity and a hypermetabolic response involving elevated temperature, heart rate, and respiratory rate that can be fatal if not recognized and treated promptly. *CACNA1S* has been noted to be associated with the following disease entities: Hypokalemic periodic paralysis, type 1 (OMIM:170400), Malignant hyperthermia susceptibility 5 (OMIM:601887), Thyrotoxic periodic paralysis, susceptibility to,1 (OMIM:188580). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability. Therefore, we have maintained the existing split into multiple disease entities. In addition, there is a more recent assertion for Congenital myopathy 18 due to dihydropyridine receptor defect (OMIM: 620246) that was not considered at the time of the precuration (9/15/2022). In this curation we examine autosomal dominant Malignant hyperthermia susceptibility 5 as a distinct disease entity. Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. We have curated eight pathogenic missense variants reported in ten probands, two of which (p.R1086H, p.T1354S) were found to segregate in families (PMID: 9199552, 11260227, 20861472,25658027,25735680,19825159). A novel homozygous mutation, p.Arg1086Ser, was identified in a 34 year old female who developed fulminant malignant hyperthermia (MH) under sevoflurane anesthesia. This is the only homozygous occurrence mentioned in the literature to date and it is unclear whether it represents a distinct molecular mechanism of disease (PMID:.20431982) This gene-disease association is supported by in vitro functional assays, expression studies, animal models, rescue models (PMID: 27129199, 2903448, 7713519, 15201141, 6329263). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

malignant hyperthermia, susceptibility to, 5MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011163

Submitter: Ambry Genetics

hypokalemic periodic paralysis, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0042979

Submitter: Labcorp Genetics (formerly Invitae)

congenital myopathy 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859514

Submitter: Labcorp Genetics (formerly Invitae)

malignant hyperthermia, susceptibility to, 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011163

Submitter: Labcorp Genetics (formerly Invitae)

congenital myopathySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0019952

Submitter: Illumina

hypokalemic periodic paralysis, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0042979

Submitter: Ambry Genetics

hypokalemic periodic paralysisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008223

Submitter: Orphanet

congenital myopathy 18STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859514

Submitter: Labcorp Genetics (formerly Invitae)

congenital myopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019952

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Malignant hyperthermia, susceptibility to, 5; Thyrotoxic period paralysis, susceptibility 1; Hypokalemic periodic paralysis, type 1AD

Manifestation: Cardiovascular; Endocrine; Musculoskeletal; Renal

Intervention: Cardiovascular; Endocrine; Pharmacogenomic; Renal

Rationale: In Malignant hyperthermia, early diagnosis, discontinuation of potent inhalation agents/succinylcholine, treatment of metabolic abnormalities, and administration of dantrolene sodium intravenously are essential to treat acute MH; In Thyrotoxic periodic paralysis, treatment of hyperthyroidism results in resolution of paralysis; In Hypokalemic periodic paralysis, paralytic crises can be treated with potassium; Dietary (eg, low sodium/carbohydrate) and medical (eg, potassium, acetazolamide) therapy can be effective; Cardiac surveillance can be beneficial

Refs: 1148686; 457125; 3855357; 3839536; 8004673; 7897626; 9199552; 11591859; 11353725; 15001631; 15534250; 18835861; 19118277; 20301512; 20301325; 22253645; 22094484; 22901280; 28012042; 31227654; 33060286; 34763287

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA1S variants in ClinVar

33 Conditions Cataloged

Malignant hyperthermia, susceptibility to, 5Total: 3040

Hypokalemic periodic paralysis, type 1Total: 2317

not providedTotal: 707

Thyrotoxic periodic paralysis, susceptibility to, 1Total: 631

Congenital myopathy 18Total: 587

Inborn genetic diseasesTotal: 266

not specifiedTotal: 187

CACNA1S-related disorderTotal: 89

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000069.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			24 clinvar	736 clinvar	15 clinvar	775
missense	13 clinvar	15 clinvar	1420 clinvar	242 clinvar	9 clinvar	1699
nonsense	23 clinvar	20 clinvar	21 clinvar			64
start loss			1 clinvar			1
frameshift	36 clinvar	20 clinvar	30 clinvar	1 clinvar		87
splice donor/acceptor (+/-2bp)		36 clinvar	25 clinvar			61
Total	72	91	1521	979	24	2687

Highest pathogenic variant AF is 0.000039651364

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000069.3	RefSeq	NP_000060.2	44	MANE Select
ENST00000362061.4	Ensembl	ENSP00000355192.3	44	MANE Select
ENST00000367338.7	Ensembl	ENSP00000356307.3	43	Standard
ENST00000367338.8	Ensembl	ENSP00000356307.3	43	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Aldosterone synthesis and secretion - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)

Biological Process

calcium ion transport
muscle contraction
regulation of ion transmembrane transport
calcium ion import
calcium ion transmembrane transport

Molecular Function

voltage-gated calcium channel activity
protein binding
calmodulin binding
high voltage-gated calcium channel activity
metal ion binding

Cellular Component

cytoplasm
plasma membrane
voltage-gated calcium channel complex
T-tubule
I band

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000362061
Coding exons: 44
Length: 73053
Individuals with no LoFs: 125639
Homozygous LoFs: 0
Heterozygous LoFs: 109
Defined: 125748
p: 0.000434

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.111	1075	1.06e+3	1.01	0.0000663	12336
Missense (PolyPhen)		460	460.25	0.99947		5288
Synonymous	-1.67	472	428	1.10	0.0000280	3641
Loss of Function	5.36	36	91.3	0.394	0.00000474	1064

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0016	notable
Latino/Admixed American	0.00043	0.00040	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00044	0.00044	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00033	0.00033	rare
South Asian	0.00059	0.00059	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. {ECO:0000250|UniProtKB:P07293}.;
Disease: DISEASE: Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Thyrotoxic periodic paralysis 1 (TTPP1) [MIM:188580]: A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease. {ECO:0000269|PubMed:15001631}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0300
RVIS EVS: -1.21
RVIS percentile EVS: 5.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.833

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High