CACNA1C

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

Basic information

Region (hg38): 12:1970771-2697950

Previous symbols: [ "CCHL1A1", "CACNL1A1", "CACNA1C-IT2" ]

Links

ENSG00000151067 ∙ NCBI:775 ∙ OMIM:114205 ∙ HGNC:1390 ∙ Uniprot:Q13936 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Timothy syndrome (Definitive), mode of inheritance: AD
• Brugada syndrome 3 (Limited), mode of inheritance: AD
• Brugada syndrome 3 (Disputed Evidence), mode of inheritance: AD
• long qt syndrome 8 (Moderate), mode of inheritance: AD
• Timothy syndrome (Strong), mode of inheritance: AD
• Brugada syndrome (Supportive), mode of inheritance: AD
• Timothy syndrome (Supportive), mode of inheritance: AD
• intellectual disability (Limited), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (Strong), mode of inheritance: AD
• Timothy syndrome (Definitive), mode of inheritance: AD
• Brugada syndrome 3 (Limited), mode of inheritance: AD
• Timothy syndrome (Strong), mode of inheritance: AD
• Brugada syndrome (Disputed Evidence), mode of inheritance: AD
• short QT syndrome (Disputed Evidence), mode of inheritance: AD
• long QT syndrome (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brugada syndrome 3; Timothy syndrome; Long QT syndrome 8	AD	Allergy/Immunology/Infectious; Cardiovascular; Pharmacogenomic	For Brugada syndrome-related manifestations, surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever; For immune deficiency (such as is described in some individuals with Timothy syndrome), preventive measures and monitoring and early and aggressive treatment of infections may be beneficial; Individuals with long QT syndrome may present with severe cardiac manifestations, including arrhythmias, syncope, and sudden death, and surveillance, preventive measures (eg, including avoidance of dangerous or excacerbating factors), and treatment (eg, including medical treatment with beta-blockers or ICD placement, which have both been described as beneficial in affected individuals) may allow early and beneficial management	Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic	1318983; 7572644; 15454078; 15863612; 17224476; 21910241; 20301690; 23677916; 25633834; 29736926; 30345660; 30513141; 34163037
In Timothy syndrome, features may be clinically recognizable, but individuals may be at risk for lethal arrhythmias; Somatic mosaicism has been described in Timothy syndrome

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA1C gene.

• Long QT syndrome (2008 variants)
• not provided (719 variants)
• Cardiovascular phenotype (708 variants)
• not specified (239 variants)
• Timothy syndrome (96 variants)
• History of neurodevelopmental disorder (43 variants)
• Timothy syndrome;Brugada syndrome 3;Long qt syndrome 8 (27 variants)
• Long qt syndrome 8 (25 variants)
• CACNA1C-related condition (23 variants)
• Brugada syndrome (23 variants)
• Brugada syndrome 3;Long qt syndrome 8;Timothy syndrome (21 variants)
• Long qt syndrome 8;Timothy syndrome;Brugada syndrome 3 (19 variants)
• Inborn genetic diseases (19 variants)
• Timothy syndrome;Long qt syndrome 8;Brugada syndrome 3 (13 variants)
• Brugada syndrome 3;Timothy syndrome;Long qt syndrome 8 (10 variants)
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (9 variants)
• Brugada syndrome 3 (8 variants)
• Long qt syndrome 8;Brugada syndrome 3;Timothy syndrome (7 variants)
• Cardiac arrhythmia (6 variants)
• Brugada syndrome 3;Timothy syndrome (5 variants)
• See cases (5 variants)
• CACNA1C-Related Disorder (4 variants)
• Intellectual disability (3 variants)
• Hypertrophic cardiomyopathy (3 variants)
• Congenital long QT syndrome (3 variants)
• Ventricular tachycardia (3 variants)
• CACNA1C-Related Disorders (2 variants)
• Long qt syndrome 8;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Timothy syndrome (2 variants)
• Wolff-Parkinson-White pattern (2 variants)
• Neurodevelopmental delay (2 variants)
• Brugada syndrome (shorter-than-normal QT interval) (2 variants)
• Sudden cardiac death (2 variants)
• Autism spectrum disorder (2 variants)
• Timothy syndrome;Brugada syndrome 3 (2 variants)
• Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Cardiomyopathy (1 variants)
• Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (1 variants)
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Brugada syndrome 3;Long qt syndrome 8;Timothy syndrome (1 variants)
• Timothy syndrome;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Brugada syndrome 3;Long qt syndrome 8 (1 variants)
• Concentric hypertrophic cardiomyopathy (1 variants)
• Brugada syndrome 3;Long qt syndrome 8;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Timothy syndrome (1 variants)
• Sudden cardiac death;Primary dilated cardiomyopathy (1 variants)
• Primary dilated cardiomyopathy (1 variants)
• Pulmonic stenosis;Intellectual disability (1 variants)
• Timothy syndrome;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Long qt syndrome 8 (1 variants)
• Hypertrophic cardiomyopathy 1 (1 variants)
• Short QT Syndrome 4 (1 variants)
• Preeclampsia (1 variants)
• Long QT syndrome;Restrictive cardiomyopathy (1 variants)
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Timothy syndrome;Brugada syndrome 3;Long qt syndrome 8 (1 variants)
• Cerebral palsy (1 variants)
• Long QT syndrome 1 (1 variants)
• Ventricular fibrillation, paroxysmal familial, type 1 (1 variants)
• Congestive heart failure (1 variants)
• Neurodevelopmental disorder (1 variants)
• Brugada syndrome 3;Long qt syndrome 8;Timothy syndrome;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (1 variants)
• Gestational diabetes mellitus uncontrolled (1 variants)
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Timothy syndrome (1 variants)
• Large for gestational age (1 variants)
• Neurodevelopmental abnormality (1 variants)
• Timothy syndrome type 1 (1 variants)
• Sudden unexplained death (1 variants)
• Short QT syndrome (1 variants)
• Timothy syndrome;Long qt syndrome 8;Brugada syndrome 3;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (1 variants)
• Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;Timothy syndrome;Long qt syndrome 8;Brugada syndrome 3 (1 variants)
• Normal pregnancy (1 variants)
• Conduction disorder of the heart (1 variants)
• Breast ductal adenocarcinoma (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia (1 variants)
• Brugada syndrome 3;Long qt syndrome 8 (1 variants)
• Amyloidosis (1 variants)
• Timothy syndrome;Brugada syndrome 3;Long qt syndrome 8;Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA1C gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	680	23	707
missense	11	19	786	41	8	865
nonsense	2	2	13			17
start loss			3			3
frameshift	5	4	23			32
inframe indel			29	1		30
splice donor/acceptor (+/-2bp)	1	3	12			16
splice region			51	90	3	144
non coding	1		15	332	203	551
Total	20	28	885	1054	234

Highest pathogenic variant AF is 0.00000657

Variants in CACNA1C

This is a list of pathogenic ClinVar variants found in the CACNA1C region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-1993289-A-C			Likely benign (Jan 01, 2024)
12-1993371-C-T		not specified	Uncertain significance (Dec 19, 2023)
12-2004352-T-C		not specified	Uncertain significance (Aug 08, 2022)
12-2004425-C-G		not specified	Uncertain significance (Sep 26, 2023)
12-2053203-G-A			Benign (Jun 19, 2018)
12-2053330-C-T		Timothy syndrome • Brugada syndrome	Uncertain significance (Jun 14, 2016)
12-2053339-T-C			Benign (Mar 03, 2015)
12-2053382-G-A			Benign (Mar 03, 2015)
12-2053484-TA-T			Benign (Mar 03, 2015)
12-2053535-C-T		not specified	Likely benign (Mar 14, 2017)
12-2053536-T-G		not specified	Likely benign (Apr 21, 2016)
12-2053560-T-C		Cardiovascular phenotype	Conflicting classifications of pathogenicity (Aug 06, 2021)
12-2053561-C-T		Cardiovascular phenotype	Uncertain significance (May 12, 2023)
12-2053563-A-C		Intellectual disability	Uncertain significance (Sep 10, 2020)
12-2053563-A-G			Uncertain significance (Apr 19, 2021)
12-2053564-T-C		Long QT syndrome • Long qt syndrome 8;Brugada syndrome 3;Timothy syndrome • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Jul 03, 2023)
12-2053565-G-C			Uncertain significance (Mar 05, 2022)
12-2053565-G-T		Long QT syndrome	Uncertain significance (Oct 22, 2023)
12-2053568-CAAT-C		Cardiovascular phenotype	Uncertain significance (Dec 11, 2020)
12-2053574-G-C		Long QT syndrome	Uncertain significance (Nov 01, 2023)
12-2053575-A-C		Long QT syndrome • Cardiovascular phenotype • Timothy syndrome;Long qt syndrome 8;Brugada syndrome 3	Uncertain significance (Dec 07, 2023)
12-2053575-AAT-A		Long QT syndrome • Timothy syndrome;Brugada syndrome 3;Long qt syndrome 8 • Cardiovascular phenotype • CACNA1C-related disorder	Conflicting classifications of pathogenicity (Jan 26, 2024)
12-2053576-A-G		Long QT syndrome • Cardiovascular phenotype	Uncertain significance (Dec 27, 2022)
12-2053579-C-G		Cardiovascular phenotype • Long QT syndrome	Uncertain significance (Dec 22, 2023)
12-2053579-C-T		Cardiovascular phenotype	Uncertain significance (Apr 08, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA1C	protein_coding	protein_coding	ENST00000347598	49	722157

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.40e-13	125735	0	9	125744	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.47	643	1.30e+3	0.495	0.0000805	14358
Missense in Polyphen		102	482.88	0.21123		5438
Synonymous	0.114	538	541	0.994	0.0000366	4272
Loss of Function	8.94	5	103	0.0487	0.00000535	1169

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.0000995	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000571	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:8392192, PubMed:7737988, PubMed:9087614, PubMed:9013606, PubMed:9607315, PubMed:12176756, PubMed:17071743, PubMed:11741969, PubMed:8099908, PubMed:12181424, PubMed:29078335, PubMed:29742403, PubMed:16299511, PubMed:20953164, PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506, PubMed:27218670). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation- contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable). {ECO:0000250|UniProtKB:P15381, ECO:0000269|PubMed:11741969, ECO:0000269|PubMed:12176756, ECO:0000269|PubMed:12181424, ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:16299511, ECO:0000269|PubMed:17071743, ECO:0000269|PubMed:17224476, ECO:0000269|PubMed:20953164, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:26253506, ECO:0000269|PubMed:27218670, ECO:0000269|PubMed:28119464, ECO:0000269|PubMed:29078335, ECO:0000269|PubMed:29742403, ECO:0000269|PubMed:7737988, ECO:0000269|PubMed:8099908, ECO:0000269|PubMed:8392192, ECO:0000269|PubMed:9013606, ECO:0000269|PubMed:9087614, ECO:0000269|PubMed:9607315, ECO:0000305}.
• Disease: DISEASE: Timothy syndrome (TS) [MIM:601005]: Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism. {ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:25260352, ECO:0000269|PubMed:25633834, ECO:0000269|PubMed:26253506}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brugada syndrome 3 (BRGDA3) [MIM:611875]: A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:17224476}. Note=The gene represented in this entry may be involved in disease pathogenesis.
• Pathway: Cortisol synthesis and secretion - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Cardiac muscle contraction - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Renin secretion - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Taste transduction - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Nicotine Pathway (Chromaffin Cell), Pharmacodynamics;Valproic Acid Pathway, Pharmacodynamics;Pathway_PA165964473;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction);Antiarrhythmic Pathway, Pharmacodynamics;Sympathetic Nerve Pathway (Neuroeffector Junction);Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Felodipine Metabolism Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Nicotine Activity on Chromaffin Cells;Alzheimers Disease;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;Calcium Regulation in the Cardiac Cell;Developmental Biology;GPCR Dopamine D1like receptor;Metabolism;Regulation of insulin secretion;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction;NCAM signaling for neurite out-growth;NCAM1 interactions;Axon guidance;Integration of energy metabolism (Consensus)

Recessive Scores

• pRec: 0.131

Intolerance Scores

• loftool: 0.000551
• rvis_EVS: -2.09
• rvis_percentile_EVS: 1.57

Haploinsufficiency Scores

• pHI: 0.663
• hipred: Y
• hipred_score: 0.694
• ghis: 0.591

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.684

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cacna1c
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: cacna1c
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased volume

Gene ontology

• Biological process: immune system development;calcium ion transport;positive regulation of cytosolic calcium ion concentration;heart development;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;embryonic forelimb morphogenesis;calcium-mediated signaling using extracellular calcium source;camera-type eye development;positive regulation of adenylate cyclase activity;regulation of insulin secretion;calcium ion transport into cytosol;cardiac conduction;calcium ion transmembrane transport via high voltage-gated calcium channel;calcium ion import;calcium ion transmembrane transport;cardiac muscle cell action potential involved in contraction;membrane depolarization during cardiac muscle cell action potential;membrane depolarization during AV node cell action potential;cell communication by electrical coupling involved in cardiac conduction;regulation of heart rate by cardiac conduction;regulation of ventricular cardiac muscle cell action potential;membrane depolarization during atrial cardiac muscle cell action potential
• Cellular component: cytoplasm;plasma membrane;integral component of plasma membrane;voltage-gated calcium channel complex;postsynaptic density;integral component of membrane;Z disc;cell junction;dendrite;perikaryon;postsynaptic membrane;L-type voltage-gated calcium channel complex
• Molecular function: voltage-gated calcium channel activity;protein binding;calmodulin binding;high voltage-gated calcium channel activity;metal ion binding;alpha-actinin binding;voltage-gated calcium channel activity involved in cardiac muscle cell action potential;voltage-gated calcium channel activity involved in AV node cell action potential