Human Gene Module / Chromosome 12 / CACNA1C

CACNA1Ccalcium channel, voltage-dependent, L type, alpha 1C subunit

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
18 / 63
Rare Variants / Common Variants
77 / 9
Aliases
CACNA1C, TS,  CACH2,  CACN2,  CaV1.2,  CCHL1A1,  CACNL1A1
Associated Syndromes
Timothy syndrome, Timothy syndrome, epilepsy/seizures, Timothy syndrome, DD
Chromosome Band
12p13.33
Associated Disorders
BPD, ID, ASD, EPS
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
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Rat
Entrez GeneRat Genome Database
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CACNA1C (63 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2 Davare MA , et al. (2001) No -
2 Primary Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism Splawski I , et al. (2004) No ASD
3 Recent Recommendation Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations Splawski I , et al. (2005) No -
4 Recent Recommendation Neuronal localization of Ca(v)1.2 L-type calcium channels in the rat basolateral amygdala Pinard CR , et al. (2005) No -
5 Recent Recommendation AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling Oliveria SF , et al. (2007) No -
6 Recent Recommendation The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2 Green EM , et al. (2007) No -
7 Recent Recommendation Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice White JA , et al. (2008) No -
8 Recent Recommendation The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels Barrett CF and Tsien RW (2008) No -
9 Recent Recommendation beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway Lipsky R , et al. (2008) No -
10 Recent Recommendation Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder Ferreira MA , et al. (2008) No -
11 Recent Recommendation Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk Moskvina V , et al. (2008) No -
12 Recent Recommendation The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation Yarotskyy V , et al. (2008) No -
13 Recent Recommendation Genetic variation in CACNA1C affects brain circuitries related to mental illness Bigos KL , et al. (2010) No -
14 Recent Recommendation The Cav? subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels Altier C , et al. (2010) No -
15 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders Schaaf CP , et al. (2011) Yes -
16 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
17 Recent Recommendation ?-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a ?-arrestin 1-mediated pathway no authors (2011) No -
18 Positive Association Genome-wide association study identifies five new schizophrenia loci Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) No -
19 Support Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome Paca SP , et al. (2011) No -
20 Support Support for calcium channel gene defects in autism spectrum disorders Lu AT , et al. (2012) Yes -
21 Recent Recommendation Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons Krey JF , et al. (2013) No -
22 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
23 Recent Recommendation Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome Boczek NJ , et al. (2013) No -
24 Recent Recommendation Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese Zhang X , et al. (2013) No -
25 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing Jiang YH , et al. (2013) Yes -
26 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 CACNA1C in brain Gershon ES , et al. (2013) No BPD
27 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder Koshimizu E , et al. (2013) Yes ID, epilepsy
28 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
29 Support - Boczek NJ et al. (2015) No -
30 Recent Recommendation CACNA1C risk variant affects reward responsiveness in healthy individuals Lancaster TM , et al. (2014) No -
31 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
32 Recent Recommendation Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons Yoshimizu T , et al. (2014) No -
33 Support Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome Wemhner K , et al. (2015) No -
34 Positive Association Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism Li J , et al. (2015) Yes -
35 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms D'Gama AM , et al. (2015) Yes -
36 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
37 Recent Recommendation The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons Lee AS , et al. (2016) No -
38 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
39 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
40 Recent Recommendation A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration Kamijo S , et al. (2018) No -
41 Support Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species Sykes L , et al. (2018) No -
42 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Stereotypies
43 Negative Association Association Study of Sequence Variants in Voltage-gated Ca2+ Channel Subunit Alpha-1C and Autism Spectrum Disorders Sayad A , et al. (2019) Yes -
44 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
45 Support An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior Buddell T , et al. (2019) No -
46 Support Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome Panagiotakos G , et al. (2019) No -
47 Support CACNA1C haploinsufficiency accounts for the common features of interstitial 12p13.33 deletion carriers Mio C , et al. (2020) No -
48 Recent Recommendation - Rodan LH et al. (2021) No ASD, ID, epilepsy/seizures
49 Support - Pode-Shakked B et al. (2021) No -
50 Support - Mahjani B et al. (2021) Yes -
51 Support - Nakagawa-Tamagawa N et al. (2021) No -
52 Support - Woodbury-Smith M et al. (2022) Yes -
53 Support - Wang C et al. (2022) No -
54 Support - Viggiano M et al. (2022) Yes -
55 Support - Zhou X et al. (2022) Yes -
56 Support - Sanderson JL et al. (2022) No ASD
57 Support - Levy RJ et al. (2022) No ASD, ADHD, epilepsy/seizures
58 Support - Klomp AJ et al. (2022) No -
59 Support - Kessi M et al. (2023) No ADHD
60 Support - Kipkemoi P et al. (2023) Yes -
61 Support - Tuncay IO et al. (2023) Yes -
62 Support - et al. () No -
63 Highly Cited N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons Hell JW , et al. (1996) No -
Rare Variants   (77)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - Simplex 31953239 Mio C , et al. (2020)
C>A - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4623+1G>A - splice_site_variant Familial Maternal - 38321498 et al. ()
c.2270C>T p.Ala757Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2669G>A p.Arg890His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.815C>T p.Ala272Val missense_variant De novo - - 37448958 Kessi M et al. (2023)
c.4549G>T p.Val1517Leu missense_variant Unknown - - 35220405 Wang C et al. (2022)
c.5563T>C p.Ser1855Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.496T>C p.Phe166Leu missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.530A>G p.Lys177Arg missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.970C>T p.Arg324Trp missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1518G>A p.Trp506Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.1207G>A p.Val403Met missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1802T>G p.Leu601Arg missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1832T>C p.Met611Thr missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1841T>C p.Leu614Pro missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1841T>G p.Leu614Arg missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.1969C>T p.Leu657Phe missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.3560T>C p.Val1187Ala missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.4222C>G p.Leu1408Val missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.4231G>C p.Val1411Leu missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.4231G>T p.Val1411Leu missense_variant De novo - - 34163037 Rodan LH et al. (2021)
c.3137T>A p.Ile1046Asn missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.3138C>G p.Ile1046Met missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.2T>C - initiator_codon_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.481C>T p.Arg161Ter stop_gained Familial Paternal - 34163037 Rodan LH et al. (2021)
c.1584G>A p.Trp528Ter stop_gained Familial Paternal - 34163037 Rodan LH et al. (2021)
c.3156+6G>C - splice_region_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.107C>T p.Ala36Val missense_variant De novo - Multiplex 35220405 Wang C et al. (2022)
c.1233G>C p.Glu411Asp missense_variant De novo - Simplex 37448958 Kessi M et al. (2023)
c.1865T>G p.Val622Gly missense_variant De novo - Simplex 37448958 Kessi M et al. (2023)
c.2227_2229delATC p.Ile743del inframe_deletion De novo - - 34163037 Rodan LH et al. (2021)
c.906G>A p.Glu302= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4553del p.Leu1518ProfsTer3 frameshift_variant De novo - - 34163037 Rodan LH et al. (2021)
c.2663+1G>C p.? splice_site_variant Unknown Not paternal - 34163037 Rodan LH et al. (2021)
c.3497T>C p.Ile1166Thr missense_variant De novo - Simplex 25260352 Boczek NJ et al. (2015)
c.911T>C p.Ile304Thr missense_variant Familial - Simplex 21624971 Schaaf CP , et al. (2011)
c.2637G>A p.Ala879= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.3476G>A p.Arg1159His missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4129dup p.Arg1377ProfsTer61 frameshift_variant De novo - - 34163037 Rodan LH et al. (2021)
c.2926delG p.Val996TrpfsTer19 frameshift_variant De novo - - 34163037 Rodan LH et al. (2021)
c.989C>T p.Thr330Met missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.1468G>A p.Gly490Arg missense_variant Familial - Simplex 21624971 Schaaf CP , et al. (2011)
c.2807T>G p.Phe936Cys missense_variant Familial - Simplex 21624971 Schaaf CP , et al. (2011)
c.3544G>C p.Val1182Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3497T>C p.Ile1166Thr missense_variant De novo - Simplex 25633834 Wemhner K , et al. (2015)
c.4761G>A p.Ala1587= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5097C>T p.Ala1699= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5292C>T p.Ser1764= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5478G>A p.Ala1826= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1204G>A p.Gly402Ser missense_variant De novo - Simplex 15863612 Splawski I , et al. (2005)
c.5624G>A p.Gly1875Asp missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.6025C>T p.Arg2009Trp missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.4966G>A p.Ala1656Thr missense_variant Familial - Simplex 21624971 Schaaf CP , et al. (2011)
c.5527G>A p.Gly1843Arg missense_variant Familial - Simplex 21624971 Schaaf CP , et al. (2011)
c.3030A>G p.Ala1010%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5306C>G p.Thr1769Ser missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.4706C>T p.Pro1569Leu missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.6272A>G p.Asn2091Ser missense_variant Unknown Not maternal - 24690944 Brett M , et al. (2014)
c.5860C>T p.Arg1989Ter stop_gained Familial Paternal Multiplex 34163037 Rodan LH et al. (2021)
c.4231G>T p.Val1411Leu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1978_1983dup p.Leu660_Phe661dup inframe_insertion De novo - - 31452935 Feliciano P et al. (2019)
c.718C>T p.Arg240Cys missense_variant Familial Maternal Simplex 21624971 Schaaf CP , et al. (2011)
c.4565G>A p.Arg1522Gln missense_variant Familial Paternal Simplex 23849776 Jiang YH , et al. (2013)
c.2437G>A p.Gly813Arg missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.5293G>A p.Ala1765Thr missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.5558T>C p.Leu1853Pro missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.6184G>A p.Val2062Ile missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.4129dup p.Arg1377ProfsTer61 frameshift_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.1216G>A p.Gly406Arg missense_variant De novo - Simplex, multiplex 15454078 Splawski I , et al. (2004)
c.6055G>A p.Val2019Ile missense_variant Familial Maternal Simplex 26845707 Alvarez-Mora MI , et al. (2016)
c.2449C>T p.Pro817Ser missense_variant Familial Maternal (1 case) Simplex 21624971 Schaaf CP , et al. (2011)
c.5242G>A p.Gly1748Ser missense_variant Familial Maternal (1 case) Simplex 21624971 Schaaf CP , et al. (2011)
c.5809C>T p.Leu1937Phe missense_variant Familial Maternal (1 case) Simplex 21624971 Schaaf CP , et al. (2011)
c.239_244delAGCGGAinsTTGCAGCTCC p.Gln80LeufsTer49 frameshift_variant De novo - - 34163037 Rodan LH et al. (2021)
c.3416G>A p.Arg1139His missense_variant Unknown - Multiplex or multi-generational 26637798 D'Gama AM , et al. (2015)
Common Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A - intron_variant - - - 26204268 Li J , et al. (2015)
c.477+119988G>C;c.567+119988G>C;c.486+119988G>C - intron_variant - - - 26204268 Li J , et al. (2015)
c.478-70203A>G;c.568-70203A>G;c.487-70203A>G G/A intron_variant - - - 23241247 Lu AT , et al. (2012)
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A - intron_variant - - - 20819988 Bigos KL , et al. (2010)
c.477+115364A>G;c.567+115364A>G;c.486+115364A>G - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.477+115699G>A;c.567+115699G>A;c.486+115699G>A - intron_variant - - - 18711365 Ferreira MA , et al. (2008)
c.478-155896A>G;c.568-155896A>G;c.487-155896A>G - intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
c.477+119988G>C;c.567+119988G>C;c.486+119988G>C C/G intron_variant - - - 21926974 Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011)
N/A - allele - - - 19065143 Moskvina V , et al. (2008)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2020
1
icon
1

Score remained at 1

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.2019] [CACNA1C haploinsufficiency accounts for the common features of interstitial 12p13.33 deletion carriers.2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior.2019] [New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Association Study of Sequence Variants in Voltage-gated Ca2+ Channel Subunit Alpha-1C and Autism Spectrum Disorders.2019]
10/1/2018
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome.2011] [Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species.2018]
10/1/2016
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
4/1/2016
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.2008] [Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for o...2008] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Genetic variation in CACNA1C affects brain circuitries related to mental illness.2010] [Genome-wide association study identifies five new schizophrenia loci.2011] [Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.2004] [Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.2005] [A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CAC...2013] [N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.1996] [A beta2 adrenergic receptor signaling complex assembled with the Ca2 channel Cav1.2.2001] [Neuronal localization of Ca(v)1.2 L-type calcium channels in the rat basolateral amygdala.2005] [AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2 channel activity and nuclear signaling.2007] [The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2.2007] [Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice.2008] [The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.2008] [beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.2008] [The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation.2008] [The Cav subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.2010] [-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a -arrestin 1-mediated pathway.2011] [Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.2013] [Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long...2013] [Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese.2013] [CACNA1C risk variant affects reward responsiveness in healthy individuals.2014] [Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.2014] [Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.2015] [Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.2008] [Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for o...2008] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Genetic variation in CACNA1C affects brain circuitries related to mental illness.2010] [Genome-wide association study identifies five new schizophrenia loci.2011] [Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.2004] [Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.2005] [A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CAC...2013] [N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.1996] [A beta2 adrenergic receptor signaling complex assembled with the Ca2 channel Cav1.2.2001] [Neuronal localization of Ca(v)1.2 L-type calcium channels in the rat basolateral amygdala.2005] [AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2 channel activity and nuclear signaling.2007] [The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2.2007] [Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice.2008] [The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.2008] [beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.2008] [The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation.2008] [The Cav subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.2010] [-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a -arrestin 1-mediated pathway.2011] [Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.2013] [Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long...2013] [Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese.2013] [CACNA1C risk variant affects reward responsiveness in healthy individuals.2014] [Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.2014] [Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.2015] [Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016]
7/1/2015
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.2013] [Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.2008] [Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for o...2008] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Genetic variation in CACNA1C affects brain circuitries related to mental illness.2010] [Genome-wide association study identifies five new schizophrenia loci.2011] [Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism.2004] [Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.2005] [A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CAC...2013] [N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons.1996] [A beta2 adrenergic receptor signaling complex assembled with the Ca2 channel Cav1.2.2001] [Neuronal localization of Ca(v)1.2 L-type calcium channels in the rat basolateral amygdala.2005] [AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2 channel activity and nuclear signaling.2007] [The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2.2007] [Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice.2008] [The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.2008] [beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.2008] [The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation.2008] [The Cav subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.2010] [-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a -arrestin 1-mediated pathway.2011] [Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons.2013] [Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long...2013] [Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese.2013] [CACNA1C risk variant affects reward responsiveness in healthy individuals.2014] [Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.2014] [Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.2015] [Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.2015]
10/1/2014
S
icon
S

Increased from S to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[CACNA1C risk variant affects reward responsiveness in healthy individuals.2014] [Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.2014]
4/1/2014
No data
icon
S

Increased from No data to S

Description

Timothy Syndrome gene (Splawski et al., 2004; PMID: 15454078); no additional evidence it is involved in idiopathic autism.

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014]
Krishnan Probability Score

Score 0.58259012642518

Ranking 558/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999843310185

Ranking 330/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9475567137724

Ranking 17324/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.37223369655839

Ranking 1765/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AHNAK AHNAK nucleoprotein Human Protein Binding 79026 Q09666
AKAP7 A kinase (PRKA) anchor protein 7 Human Protein Binding 9465 O43687
ANKRD35 ankyrin repeat domain 35 Human Protein Binding 148741 Q8N283
BIN1 bridging integrator 1 Human Protein Binding 274 O00499
BSG basigin (Ok blood group) Human Protein Binding 682 P35613
C18orf32 chromosome 18 open reading frame 32 Human Protein Binding 497661 Q8TCD1
CABP1 calcium binding protein 1 Human Protein Binding 9478 Q9NZU7
CACNB1 calcium channel, voltage-dependent, beta 1 subunit Human Protein Binding 775 Q13936
CACNB2 calcium channel, voltage-dependent, beta 2 subunit Human Protein Binding 783 Q08289
CACNB3 calcium channel, voltage-dependent, beta 3 subunit Human Protein Binding 784 P54284
CACNB4 calcium channel, voltage-dependent, beta 4 subunit Human Protein Binding 785 O00305
Camk2a calcium/calmodulin-dependent protein kinase II alpha Rat Protein Binding 25400 P11275
DNAJA3 DnaJ (Hsp40) homolog, subfamily A, member 3 Human Protein Binding 9093 Q96EY1
EFEMP1 EGF containing fibulin-like extracellular matrix protein 1 Human Protein Binding 2202 Q12805
EIF3E eukaryotic translation initiation factor 3, subunit E Human Protein Binding 3646 P60228
FHL2 four and a half LIM domains 2 Human Protein Binding 2274 Q14192
GABBR2 gamma-aminobutyric acid (GABA) B receptor, 2 Human Protein Binding 9568 O75899
IFT88 intraflagellar transport 88 homolog (Chlamydomonas) Human Protein Binding 8100 Q13099
KCNIP2 Kv channel interacting protein 2 Human Protein Binding 30819 Q9NS61
KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1 Human Protein Binding 3778 Q12791
NUP133 nucleoporin 133kDa Human Protein Binding 55746 Q8WUM0
PIKFYVE phosphoinositide kinase, FYVE finger containing Human Protein Binding 200576 Q9Y2I7
Ppm1a protein phosphatase 1A, magnesium dependent, alpha isoform Rat Protein Binding 24666 P20650
PPP2R4 protein phosphatase 2A activator, regulatory subunit 4 Human Protein Binding 5524 Q15257
PPP3CB protein phosphatase 3, catalytic subunit, beta isozyme Human Protein Binding 5532 P16298
PRKACA protein kinase, cAMP-dependent, catalytic, alpha Human Protein Modification 5566 P17612
RIC3 resistance to inhibitors of cholinesterase 3 homolog (C. elegans) Human Protein Binding 79608 Q7Z5B4
RIMS2 regulating synaptic membrane exocytosis 2 Human Protein Binding 9699 Q9UQ26
RYR1 ryanodine receptor 1 (skeletal) Rabbit Protein Binding 100009540 P11716
S100A10 S100 calcium binding protein A10 Human Protein Binding 6281 P60903
SRI sorcin Human Protein Binding 6717 P30626
SRRT serrate RNA effector molecule homolog (Arabidopsis) Human Protein Binding 51593 Q9BXP5
STIM1 stromal interaction molecule 1 Human Protein Binding 6786 Q13586
TNIP2 TNFAIP3 interacting protein 2 Human Protein Binding 79155 Q8NFZ5
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