CACNA1C
Homo sapiens
Gene Name: calcium channel, voltage-dependent, L type, alpha 1C subunit
Aliases: TS, CACH2, CACN2, CaV1.2, CCHL1A1, CACNL1A1
Chromosome No: 12
Chromosome Band: 12p13.33
Genetic Category: Syndromic-Genetic Association-Genetic Association/Functional-Rare Single Gene variant-Functional-Syndromic/functional-Rare single gene variant/Functional
Associated Syndrome(s): Timothy syndrome
Aliases: TS, CACH2, CACN2, CaV1.2, CCHL1A1, CACNL1A1
Chromosome No: 12
Chromosome Band: 12p13.33
Genetic Category: Syndromic-Genetic Association-Genetic Association/Functional-Rare Single Gene variant-Functional-Syndromic/functional-Rare single gene variant/Functional
Associated Syndrome(s): Timothy syndrome
Summary Statistics:
ASD Reports: 63
Recent Reports: 22
Annotated variants: 86
Associated CNVs: 8
Evidence score: 4
ASD Reports: 63
Recent Reports: 22
Annotated variants: 86
Associated CNVs: 8
Evidence score: 4
| Associated Disorders: |
|
Relevance to Autism
This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, mutation of the CACNA1C gene has been found to be associated with Timothy syndrome, patients which all also fall under the category of ASD. In addition, several studies have shown a genetic association between the CACNA1C gene and schizophrenia as well as bipolar disorder.
Molecular Function
This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.
Timothy syndrome
ASD
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Positive Association
Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.
ASD
Positive Association
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
ASD, ADHD, BPD, MDD, SCZ
Positive Association
Genome-wide association study identifies five new schizophrenia loci.
SCZ, BPD
Negative Association
Association Study of Sequence Variants in Voltage-gated Ca2+ Channel Subunit Alpha-1C and Autism Spectrum Disorders.
ASD
Support
Novel Timothy syndrome mutation leading to increase in CACNA1C window current
Timothy syndrome, epilepsy/seizures
Support
The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome
Timothy syndrome
ASD
Support
Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species.
Support
Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.
ASD
Support
A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies
DD, ID, epilepsy/seizures
Support
Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...
DD, ID, ASD
MCA
Support
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
DD, ID, PDD
Support
CACNA1C haploinsufficiency accounts for the common features of interstitial 12p13.33 deletion carriers.
DD
Support
Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...
ASD
ID, epilepsy
Support
Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility
ASD
Support
Comprehensive molecular testing in patients with high functioning autism spectrum disorder.
ASD
Support
Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.
Timothy syndrome
Support
Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.
ASD
Support
Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder
SCZ
Support
Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.
ASD
Support
An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.
Support
Support for calcium channel gene defects in autism spectrum disorders.
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.
Timothy syndrome, DD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.
Support
Involvement of Calcium-Dependent Pathway and β Subunit-Interaction in Neuronal Migration and Callosal Projection Deficits Caused by the Cav1.2 I1166T Mutation in Developing Mouse Neocortex
Timothy syndrome
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder
Timothy syndrome, DD
ASD, ADHD, epilepsy/seizures
Support
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.
ID, epilepsy/seizures, speech delay
Stereotypies
Support
Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.
Epilepsy
Support
Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder
ASD
Highly Cited
N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.
Highly Cited
A beta2 adrenergic receptor signaling complex assembled with the Ca2 channel Cav1.2.
Recent Recommendation
Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice.
Recent Recommendation
Genetic variation in CACNA1C affects brain circuitries related to mental illness.
SCZ
Recent Recommendation
A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CAC...
Timothy syndrome
BPD
Recent Recommendation
The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2.
Recent Recommendation
The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation.
Recent Recommendation
Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese.
Recent Recommendation
AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2 channel activity and nuclear signaling.
Recent Recommendation
Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations
DD
ASD, ID, epilepsy/seizures
Recent Recommendation
Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for o...
BPD
Recent Recommendation
Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long...
Recent Recommendation
Neuronal localization of Ca(v)1.2 L-type calcium channels in the rat basolateral amygdala.
Recent Recommendation
A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration.
Recent Recommendation
Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.
BPD
Recent Recommendation
Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.
Recent Recommendation
Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.
Timothy syndrome
Recent Recommendation
The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons.
Recent Recommendation
beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.
Recent Recommendation
-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a -arrestin 1-mediated pathway.
Recent Recommendation
Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.
Recent Recommendation
The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.
Recent Recommendation
The Cav subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.
Recent Recommendation
CACNA1C risk variant affects reward responsiveness in healthy individuals.
Rare
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
GEN031R001
missense_variant
c.1216G>A
p.Gly406Arg
De novo
Simplex, multiplex
GEN031R006
missense_variant
c.2449C>T
p.Pro817Ser
Familial
Maternal (1 case)
Simplex
GEN031R009
missense_variant
c.5242G>A
p.Gly1748Ser
Familial
Maternal (1 case)
Simplex
GEN031R010
missense_variant
c.5293G>A
p.Ala1765Thr
Familial
Paternal
Simplex
GEN031R012
missense_variant
c.5558T>C
p.Leu1853Pro
Familial
Paternal
Simplex
GEN031R013
missense_variant
c.5809C>T
p.Leu1937Phe
Familial
Maternal (1 case)
Simplex
GEN031R014
missense_variant
c.6184G>A
p.Val2062Ile
Familial
Paternal
Simplex
GEN031R027
missense_variant
c.3416G>A
p.Arg1139His
Unknown
Multiplex or multi-generational
GEN031R029
missense_variant
c.6055G>A
p.Val2019Ile
Familial
Maternal
Simplex
GEN031R048
frameshift_variant
c.239_244delAGCGGAinsTTGCAGCTCC
p.Gln80LeufsTer49
De novo
Common
Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
GEN031C001
intron_variant
rs1006737
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A
4,387 cases and 6,209 controls from combined WTCCC, STEP-UCL and ED-DUB-STEP2 studies
Discovery
GEN031C003
intron_variant
rs1006737
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A
CBDB-NIMHSS
Discovery
GEN031C004
intron_variant
rs10848653
c.478-70203A>G;c.568-70203A>G;c.487-70203A>G
G/A
2781 Caucasian parent/child trios (1103 from 543 AGRE families and 1678 from 1651 AGP families)
Discovery
GEN031C005
intron_variant
rs1024582
c.478-155896A>G;c.568-155896A>G;c.487-155896A>G
Pyschiatrics Genomic Consortium (PGC): 33,332 cases (with ASD, ADHD, bipolar disorder, major depressive disorder, and schizophrenia) and 27,888 controls
Discovery
GEN031C006
intron_variant
rs4765905
c.477+119988G>C;c.567+119988G>C;c.486+119988G>C
C/G
16,374 cases with schizophrenia, schizoaffective disorder or bipolar disorder and 14,044 controls
Discovery
GEN031C007
intron_variant
rs1006737
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A
553 ASD trios of Chinese Han descent
Discovery
GEN031C008
intron_variant
rs4765905
c.477+119988G>C;c.567+119988G>C;c.486+119988G>C
554 ASD trios of Chinese Han descent
Discovery
GEN031C009
intron_variant
rs2007044
c.477+115364A>G;c.567+115364A>G;c.486+115364A>G
40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets)
Discovery
