CAMTA1

Summary

CAMTA1 (calmodulin binding transcription activator 1, HGNC:18806) is a protein-coding gene on chromosome 1p36.31-p36.23, encoding Calmodulin-binding transcription activator 1 (Q9Y6Y1). Transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene contains a CG1 DNA-binding domain, a transcription factor immunoglobulin domain, ankyrin repeats, and calmodulin-binding IQ motifs. The encoded protein is thought to be a transcription factor and may be a tumor suppressor. However, a translocation event is sometimes observed between this gene and the WWTR1 gene, with the resulting WWTR1-CAMTA1 oncoprotein leading to epithelioid hemangioendothelioma, a malignant vascular cancer.

Source: NCBI Gene 23261 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar dysfunction with variable cognitive and behavioral abnormalities (Definitive, ClinGen)
• GWAS associations: 32
• Clinical variants (ClinVar): 977 total — 62 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 80
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015215

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18806
Approved symbol	CAMTA1
Name	calmodulin binding transcription activator 1
Location	1p36.31-p36.23
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0833
Ensembl gene	ENSG00000171735
Ensembl biotype	protein_coding
OMIM	611501
Entrez	23261

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 20 protein_coding, 9 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay

ENST00000303635, ENST00000461311, ENST00000461580, ENST00000467267, ENST00000467404, ENST00000470648, ENST00000472283, ENST00000473578, ENST00000476163, ENST00000476864, ENST00000482934, ENST00000486138, ENST00000490738, ENST00000490905, ENST00000495233, ENST00000557126, ENST00000700414, ENST00000700415, ENST00000700416, ENST00000700417, ENST00000700418, ENST00000700419, ENST00000700420, ENST00000700421, ENST00000700422, ENST00000700423, ENST00000700424, ENST00000700425, ENST00000700444, ENST00000700445, ENST00000700446, ENST00000700447, ENST00000700448, ENST00000700449, ENST00000710284, ENST00000710285

RefSeq mRNA: 24 — MANE Select: NM_015215 NM_001195563, NM_001242701, NM_001349608, NM_001349609, NM_001349610, NM_001349612, NM_001349613, NM_001349614, NM_001349615, NM_001349616, NM_001349617, NM_001349618, NM_001349619, NM_001349620, NM_001349621, NM_001349622, NM_001349623, NM_001349624, NM_001349625, NM_001349626, NM_001349627, NM_001410737, NM_001410738, NM_015215

CCDS: CCDS30576, CCDS55574, CCDS55575, CCDS85922, CCDS90849, CCDS90850, CCDS90851, CCDS90852, CCDS90853, CCDS90854

Canonical transcript exons

ENST00000303635 — 23 exons

Exon	Start	End
ENSE00003563207	6820181	6820250
ENSE00004011028	7732448	7732599
ENSE00004011029	7467830	7467901
ENSE00004011030	6825092	6825210
ENSE00004011031	7661726	7661866
ENSE00004011032	7736931	7737009
ENSE00004011033	7663353	7665199
ENSE00004011034	7091304	7091371
ENSE00004011035	7752459	7752533
ENSE00004011036	7737255	7737570
ENSE00004011037	7640400	7640553
ENSE00004011038	7736344	7736540
ENSE00004011039	7677599	7677733
ENSE00004011041	7755638	7755668
ENSE00004011042	7745845	7746091
ENSE00004011046	6785454	6785575
ENSE00004011047	7670911	7671037
ENSE00004011048	7766459	7769706
ENSE00004011050	7747710	7747781
ENSE00004011051	7744835	7745022
ENSE00004011052	7751199	7751392
ENSE00004011053	7737959	7738482
ENSE00004011054	7249491	7249626

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.5585 / max 316.6610, expressed in 1825 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
415	37.6268	1823
434	3.4835	686
416	1.4128	947
417	1.3568	852
414	0.8565	597
433	0.3726	181
418	0.3636	191
420	0.0564	21
419	0.0181	9
431	0.0115	3

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.87	gold quality
postcentral gyrus	UBERON:0002581	98.50	gold quality
heart right ventricle	UBERON:0002080	98.43	gold quality
popliteal artery	UBERON:0002250	98.35	gold quality
tibial artery	UBERON:0007610	98.35	gold quality
aorta	UBERON:0000947	98.20	gold quality
right coronary artery	UBERON:0001625	98.18	gold quality
palpebral conjunctiva	UBERON:0001812	98.16	gold quality
parietal lobe	UBERON:0001872	98.13	gold quality
thoracic aorta	UBERON:0001515	98.02	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.02	gold quality
ascending aorta	UBERON:0001496	98.01	gold quality
vena cava	UBERON:0004087	98.01	gold quality
lower esophagus	UBERON:0013473	98.01	gold quality
descending thoracic aorta	UBERON:0002345	98.00	gold quality
right atrium auricular region	UBERON:0006631	97.98	gold quality
left coronary artery	UBERON:0001626	97.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.90	gold quality
coronary artery	UBERON:0001621	97.87	gold quality
apex of heart	UBERON:0002098	97.78	gold quality
cauda epididymis	UBERON:0004360	97.77	gold quality
corpus epididymis	UBERON:0004359	97.75	gold quality
pons	UBERON:0000988	97.74	gold quality
jejunal mucosa	UBERON:0000399	97.73	gold quality
adult organism	UBERON:0007023	97.73	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.73	gold quality
monocyte	CL:0000576	97.66	gold quality
biceps brachii	UBERON:0001507	97.66	gold quality
eye	UBERON:0000970	97.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.60	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	1741.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ANXA2
HSP90B2P
NELFE
NPPA	Activation
RAB18

miRNA regulators (miRDB)

416 targeting CAMTA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-1184	99.99	68.19	1458

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• FLJ10737 and CAMTA1 genes on 1p36.31-p36.23 are candidate tumor suppressor genes of neuroblastoma (PMID:12964007)
• no evidence for somatic mutations in FLJ10737 in neuroblastoma (PMID:17222547)
• validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memory. (PMID:17470457)
• Findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. (PMID:21385898)
• the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue, and visceral location (PMID:21584898)
• CAMTA1 was identified as an miR-9/9* and miR- 17 target. CAMTA1 expression led to reduced neurosphere formation and growth of human glioblastomas in nude mice. Consistently, CAMTA1 and NPPA expression correlate with patient survival. (PMID:21857646)
• Results indicate that CAMTA1 genotype is associated with cognitive function in older adults with cardiovascular disease, because carriers of the T allele performed more poorly on tests of attention, executive function, and psychomotor speed. (PMID:21951953)
• Using reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequencing, we confirmed an identical WWTR1-CAMTA1 fusion transcript product from different nodules in each patient. (PMID:22429593)
• The authors present evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. (PMID:22693284)
• Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+) signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+)-dependent intermediate, up-regulation of CAMTA1. (PMID:22715383)
• Intragenic CAMTA1 deletions are associated with a spectrum of neurobehavioral phenotypes (PMID:24738973)
• Epithelioid hemangioendothelioma, it’s potential mimickers, and other benign or malignant vascular tumors showed strong and diffuse CAMTA1 expression, nullifying it’s potential use as an adjunct in the differential diagnosis. (PMID:25110239)
• Report CAMTA1-WWTR1 gene fusion in thoracic epithelioid hemangioendothelioma but not epithelioid angiosarcoma. (PMID:25353289)
• we demonstrate additional structural complexity in WWTR1-CAMTA1 fusion transcripts in epithelioid haemangioendothelioma (PMID:25817592)
• Nuclear CAMTA1 expression is sensitive and highly specific for epithelioid haemangioendothelioma and can be applied to diagnostic immunohistochemistry in epithelioid tumours. (PMID:25879300)
• Our findings elucidate the mechanistic basis of the oncogenic properties of TAZ-CAMTA1 fusion (PMID:25961935)
• Nuclear expression of CAMTA1 can be used in the differential diagnosis of epithelioid hemangioendotheliomas. (PMID:26414223)
• TFE3 gene translocations are compossible with CAMTA1 gene rearrangements in Epithelioid hemangioendotheliomas. (PMID:26840265)
• This GWAS identified 2 loci at 10q23 (rs139550538; P = 1.87 x 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 x 10-8). genome-wide levels of significance that influence survival in patients with ALS. (PMID:27244217)
• our data reveal that TDP-43 can function as an mRNA-specific translational enhancer. Moreover, since CAMTA1 and DENND4A are linked to neurodegeneration, they suggest that this function could contribute to disease. (PMID:30357366)
• the findings in this study suggest that hypomethylated CpG sites, present in four regions of the FOXP3 locus, CAMTA1 and FUT7 gene regions, can potentially be used to distinguish subsets of CD4+ T lymphocytes in both sexes. (PMID:30455694)
• CAMTA1 is a highly sensitive and specific marker for diagnosis of hepatic EHE. It is helpful for differentiation of hepatic EHE and angiosarcoma, especially in small biopsy samples. (PMID:31662570)
• De novo variants in CAMTA1 cause a syndrome variably associated with spasticity, ataxia, and intellectual disability. (PMID:32157189)
• Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants. (PMID:33131045)
• CAMTA1, a novel antitumor gene, regulates proliferation and the cell cycle in glioma by inhibiting AKT phosphorylation. (PMID:33316386)
• Myoclonic dystonia phenotype related to a novel calmodulin-binding transcription activator 1 sequence variant. (PMID:33677721)
• TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex. (PMID:33913810)
• The role of Calmodulin Binding Transcription Activator 1 (CAMTA1) gene and its putative genetic partners in the human nervous system. (PMID:35949142)
• CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review. (PMID:38044714)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	camta1b	ENSDARG00000007824
danio_rerio	camta1a	ENSDARG00000077428
mus_musculus	Camta1	ENSMUSG00000014592
rattus_norvegicus	Camta1	ENSRNOG00000018602

Paralogs (1): CAMTA2 (ENSG00000108509)

Protein

Protein identifiers

Calmodulin-binding transcription activator 1 — Q9Y6Y1 (reviewed: Q9Y6Y1)

All UniProt accessions (25): Q9Y6Y1, A0A0C4DGL0, A0A8V8TPN7, A0A8V8TPP2, A0A8V8TPQ2, A0A8V8TPQ7, A0A8V8TQ65, A0A8V8TQ84, A0A8V8TQ87, A0A8V8TQ98, A0A8V8TQA4, A0A8V8TQX1, A0A8V8TQX5, A0A8V8TQX9, A0A8V8TR75, A0A8V8TR82, A0A8V8TR85, A0AA34QVU6, A0AA34QVZ9, G3V297, H0YJG5, H0YJK7, H0YJR7, H0YJV1, H0YJY7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator.

Subunit / interactions. May interact with calmodulin.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Normally expressed in non-neoplastic adult central nervous system tissues: detected in whole brain, cerebellum, brain cortex, occipital lobe, frontal lobe, temporal lobe, putamen. Expression levels are low in oligodendroglial tumors, and are reduced by half in oligodendroglioma and astrocytoma cases with 1p loss of heterozygosity. Detected in neuroblastic-type cultured neuroblastoma cells. Expressed in heart and kidney.

Disease relevance. Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) [MIM:614756] An autosomal dominant neurodevelopmental disorder characterized by mildly delayed psychomotor development, early onset of cerebellar ataxia, and intellectual disability later in childhood and adult life. Other features may include neonatal hypotonia, dysarthria, and dysmetria. Brain imaging in some patients shows cerebellar atrophy. Dysmorphic facial features are variable. The disease is caused by variants affecting the gene represented in this entry.

Induction. Detected at low levels at interphase and in resting cells. Up-regulated during S phase and mitosis. Levels decrease at the end of mitosis.

Miscellaneous. A very small segment of 1p36 located within CAMTA1 is deleted in all oligodendroglial tumors with 1p LOH. This minimal deleted region (MDR) also overlaps the neuroblastoma 1p36 MDR. CAMTA1 shows no evidence of inactivation by somatic mutations.

Similarity. Belongs to the CAMTA family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y6Y1-1	1	yes
Q9Y6Y1-2	2
Q9Y6Y1-3	3
Q9Y6Y1-4	4

RefSeq proteins (24): NP_001182492, NP_001229630, NP_001336537, NP_001336538, NP_001336539, NP_001336541, NP_001336542, NP_001336543, NP_001336544, NP_001336545, NP_001336546, NP_001336547, NP_001336548, NP_001336549, NP_001336550, NP_001336551, NP_001336552, NP_001336553, NP_001336554, NP_001336555, NP_001336556, NP_001397666, NP_001397667, NP_056030* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR002110	Ankyrin_rpt	Repeat
IPR002909	IPT_dom	Domain
IPR005559	CG-1_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00612, PF01833, PF03859, PF12796

UniProt features (37 total): strand 9, splice variant 6, domain 4, region of interest 4, compositionally biased region 4, sequence variant 4, repeat 3, chain 1, short sequence motif 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CXK	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6Y1-F1	51.94	0.12

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 499 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, BROWNE_HCMV_INFECTION_12HR_UP, CCATCCA_MIR432, MORF_RAD51L3, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GTGCCTT_MIR506, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, MORF_CTSB, TGTGTGA_MIR377, MORF_PRKCA, AAAGACA_MIR511, BASSO_HAIRY_CELL_LEUKEMIA_UP

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), neuromuscular process controlling balance (GO:0050885), positive regulation of calcineurin-NFAT signaling cascade (GO:0070886)

GO Molecular Function (5): double-stranded DNA binding (GO:0003690), transcription coregulator activity (GO:0003712), sequence-specific DNA binding (GO:0043565), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
DNA binding	2
regulation of DNA-templated transcription	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
musculoskeletal movement	1
neuromuscular process	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
positive regulation of calcineurin-mediated signaling	1
transcription regulator activity	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAMTA1	WWTR1	Q9GZV5	864
CAMTA1	CALM1	P02593	761
CAMTA1	TFE3	P19532	714
CAMTA1	CALML3	P27482	597
CAMTA1	CALML5	Q9NZT1	596
CAMTA1	CALML6	Q8TD86	595
CAMTA1	CALML4	Q96GE6	595
CAMTA1	NPPA	P01160	579
CAMTA1	YAP1	P46937	540
CAMTA1	ANK1	P16157	529
CAMTA1	ANK3	Q12955	527
CAMTA1	ANK2	Q01484	525
CAMTA1	CASZ1	Q86V15	498
CAMTA1	CAMTA2	O94983	487
CAMTA1	EHBP1L1	Q8N3D4	482

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
IPO5	SLC27A2	psi-mi:“MI:0914”(association)	0.530
CHCHD4	ENSA	psi-mi:“MI:0914”(association)	0.530
PEX14	CAMTA1	psi-mi:“MI:0407”(direct interaction)	0.440
ALB	CNOT1	psi-mi:“MI:0914”(association)	0.350
N	RBM47	psi-mi:“MI:0914”(association)	0.350
AIFM1	HSPA12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): CAMTA1 (Affinity Capture-RNA), CAMTA1 (Affinity Capture-RNA), CAMTA1 (Proximity Label-MS), CAMTA1 (Affinity Capture-RNA), CAMTA1 (Affinity Capture-MS), CAMTA1 (Affinity Capture-MS), CAMTA1 (Affinity Capture-MS), CAMTA1 (Affinity Capture-MS), CAMTA1 (Protein-peptide), CAMTA1 (Affinity Capture-RNA), CAMTA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IBL7, A2A891, A3RK74, A4L7N3, B5DE09, E1BPQ1, G3V7R4, O15014, O43524, P11420, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P70365, P98180, Q01978, Q12778, Q14135, Q15596, Q15788, Q4PJW2, Q53TQ3, Q60420, Q60722, Q61026, Q61286, Q62655, Q66IY8, Q66JJ0, Q6DIH5, Q6EUW2, Q6NZT6, Q6PCG7, Q7T2G1, Q7ZXS3, Q80V24

Diamond homologs: A2A891, H2KY84, O23463, O94983, Q6NPP4, Q7XHR2, Q80Y50, Q8GSA7, Q9FY74, Q9FYG2, Q9LSP8, Q9Y6Y1, P62294, Q10728, Q9DBR7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CAMTA1	down-regulates	Proliferation
CAMTA1	up-regulates	Differentiation
CAMTA1	“up-regulates quantity by expression”	NPPA	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — LMS, PRAD.

Clinical variants and AI predictions

ClinVar

977 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	45
Uncertain significance	493
Likely benign	251
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068627	NM_015215.4(CAMTA1):c.2944C>T (p.Arg982Ter)	Pathogenic
1298401	NM_015215.4(CAMTA1):c.4813C>T (p.Arg1605Ter)	Pathogenic
1342305	NM_015215.4(CAMTA1):c.180_183del (p.Leu61fs)	Pathogenic
1342309	NM_015215.4(CAMTA1):c.404A>G (p.Glu135Gly)	Pathogenic
1451348	NC_000001.10:g.(?6845591)(6947785_?)del	Pathogenic
1685599	NM_015215.4(CAMTA1):c.3142C>T (p.Arg1048Ter)	Pathogenic
1694485	NM_015215.4(CAMTA1):c.1156del (p.Val386fs)	Pathogenic
1723214	NM_015215.4(CAMTA1):c.1798dup (p.Ser600fs)	Pathogenic
1804080	NM_015215.4(CAMTA1):c.2416_2419del (p.Ser806fs)	Pathogenic
1808723	GRCh37/hg19 1p36.23(chr1:7526232-8290521)x1	Pathogenic
2331583	NM_015215.4(CAMTA1):c.501G>A (p.Trp167Ter)	Pathogenic
2446028	NM_015215.4(CAMTA1):c.2822del (p.Asn941fs)	Pathogenic
2582483	NM_015215.4(CAMTA1):c.1828C>T (p.Gln610Ter)	Pathogenic
2630516	NM_015215.4(CAMTA1):c.2685_2686dup (p.Gln896fs)	Pathogenic
2685310	GRCh37/hg19 1p36.23(chr1:7480054-7659291)x1	Pathogenic
2685321	GRCh37/hg19 1p36.23(chr1:7490132-7800890)x1	Pathogenic
280872	NM_015215.4(CAMTA1):c.882del (p.Tyr297fs)	Pathogenic
2831056	NM_015215.4(CAMTA1):c.2577dup (p.Thr860fs)	Pathogenic
2831073	NM_015215.4(CAMTA1):c.2638del (p.Trp880fs)	Pathogenic
2981181	NM_015215.4(CAMTA1):c.576C>A (p.Cys192Ter)	Pathogenic
3063055	GRCh37/hg19 1p36.31(chr1:6727645-6854433)x1	Pathogenic
3063366	GRCh37/hg19 1p36.31(chr1:6810718-7036045)x1	Pathogenic
3253493	NM_015215.4(CAMTA1):c.4614C>A (p.Tyr1538Ter)	Pathogenic
3254720	NM_015215.4(CAMTA1):c.2072_2075del (p.Thr691fs)	Pathogenic
3376151	NM_015215.4(CAMTA1):c.578del (p.Gly193fs)	Pathogenic
3390303	GRCh37/hg19 1p36.23(chr1:7721786-7721926)x1	Pathogenic
3484605	NM_015215.4(CAMTA1):c.725_728dup (p.Val244fs)	Pathogenic
3640621	NM_015215.4(CAMTA1):c.131del (p.Ser44fs)	Pathogenic
37006	NC_000001.10:g.7119268_7200395del	Pathogenic
37007	NC_000001.10:g.6882372_7422115dup	Pathogenic

SpliceAI

5758 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6785571:GGAAG:G	donor_gain	1.0000
1:6785572:GAAG:G	donor_gain	1.0000
1:6785572:GAAGG:G	donor_gain	1.0000
1:6785573:A:T	donor_gain	1.0000
1:6785574:AGGTA:A	donor_loss	1.0000
1:6785575:GGT:G	donor_loss	1.0000
1:6785576:G:GA	donor_loss	1.0000
1:6785576:G:GG	donor_gain	1.0000
1:6825090:A:AG	acceptor_gain	1.0000
1:6825091:G:GG	acceptor_gain	1.0000
1:6825207:TGAGG:T	donor_loss	1.0000
1:6825210:GGTA:G	donor_loss	1.0000
1:6825212:T:A	donor_loss	1.0000
1:6885252:G:GT	donor_gain	1.0000
1:7249618:G:GT	donor_gain	1.0000
1:6785574:AG:A	donor_gain	0.9900
1:6785575:GG:G	donor_gain	0.9900
1:6785577:T:A	donor_loss	0.9900
1:6801182:G:T	donor_gain	0.9900
1:6820180:GAGC:G	acceptor_gain	0.9900
1:6825086:TTGTA:T	acceptor_loss	0.9900
1:6825087:TGTAG:T	acceptor_loss	0.9900
1:6825088:GTAG:G	acceptor_loss	0.9900
1:6825089:TA:T	acceptor_loss	0.9900
1:6825090:AG:A	acceptor_loss	0.9900
1:6825090:AGAT:A	acceptor_gain	0.9900
1:6825091:GAT:G	acceptor_gain	0.9900
1:6825091:GATG:G	acceptor_gain	0.9900
1:6825214:GA:G	donor_gain	0.9900
1:6886320:G:GT	donor_gain	0.9900

AlphaMissense

11076 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6825196:T:A	W74R	1.000
1:6825196:T:C	W74R	1.000
1:6825197:G:C	W74S	1.000
1:6825198:G:C	W74C	1.000
1:6825198:G:T	W74C	1.000
1:6825207:T:A	N77K	1.000
1:6825207:T:G	N77K	1.000
1:7091308:T:G	I80S	1.000
1:7091320:T:C	L84S	1.000
1:7091328:T:C	F87L	1.000
1:7091329:T:C	F87S	1.000
1:7091330:T:A	F87L	1.000
1:7091330:T:G	F87L	1.000
1:7091346:T:A	W93R	1.000
1:7091346:T:C	W93R	1.000
1:7091347:G:C	W93S	1.000
1:7091348:G:C	W93C	1.000
1:7091348:G:T	W93C	1.000
1:7091350:T:C	L94P	1.000
1:7091371:G:C	R101T	1.000
1:7249491:A:C	R101S	1.000
1:7249491:A:T	R101S	1.000
1:7249492:C:T	P102S	1.000
1:7249493:C:A	P102Q	1.000
1:7249501:G:C	G105R	1.000
1:7249502:G:A	G105D	1.000
1:7249502:G:T	G105V	1.000
1:7249511:T:A	I108K	1.000
1:7249511:T:G	I108R	1.000
1:7249514:T:A	L109H	1.000

dbSNP variants (sampled 300 via entrez): RS1000001628 (1:7542430 T>C,G), RS1000005983 (1:7395564 A>G), RS1000006806 (1:7288355 G>A), RS1000006903 (1:7434700 C>G), RS1000011586 (1:7437328 G>A), RS1000012517 (1:6882403 G>A), RS1000016386 (1:6998560 G>T), RS1000019844 (1:7469306 T>C), RS1000019985 (1:7184522 TAAAA>T,TAAA), RS1000020706 (1:7312826 G>A,C), RS1000021813 (1:7027277 T>C), RS1000022991 (1:7120003 C>T), RS1000024334 (1:6862550 T>G), RS1000024605 (1:7762904 A>T), RS1000024952 (1:6960504 G>A)

Disease associations

OMIM: gene MIM:611501 | disease phenotypes: MIM:614756, MIM:618505

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar dysfunction with variable cognitive and behavioral abnormalities	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cerebellar dysfunction with variable cognitive and behavioral abnormalities	Definitive	AD

Mondo (6): cerebellar dysfunction with variable cognitive and behavioral abnormalities (MONDO:0013886), neurodevelopmental disorder (MONDO:0700092), epilepsy (MONDO:0005027), neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities (MONDO:0032790), intellectual disability (MONDO:0001071), hereditary ataxia (MONDO:0100309)

Orphanet (3): Non-progressive cerebellar ataxia with intellectual disability (Orphanet:314647), Hereditary ataxia (Orphanet:183518), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000445	Wide nose
HP:0000454	Flared nostrils
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000527	Long eyelashes
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001588_5	Periodontal microbiota	5.000000e-06
GCST001840_9	Stearic acid (18:0) levels	1.000000e-06
GCST002425_1	Puberty onset	5.000000e-06
GCST002427_2	Puberty onset (breast development)	9.000000e-07
GCST002682_1	Tourette’s syndrome or obsessive-compulsive disorder	8.000000e-06
GCST003121_18	Alcohol dependence	9.000000e-06
GCST003262_254	Post bronchodilator FEV1	2.000000e-06
GCST003632_2	Survival in sporadic amyotrophic lateral sclerosis	4.000000e-08
GCST003992_5	Photic sneeze reflex	1.000000e-10
GCST004131_79	Inflammatory bowel disease	1.000000e-12
GCST004132_92	Crohn’s disease	3.000000e-06
GCST004133_62	Ulcerative colitis	4.000000e-09
GCST004599_239	Mean platelet volume	9.000000e-18
GCST004616_103	Platelet distribution width	9.000000e-10
GCST005790_75	Rosacea symptom severity	7.000000e-07
GCST006627_52	Diastolic blood pressure	5.000000e-10
GCST006940_12	Neurociticism	1.000000e-09
GCST006950_32	Feeling worry	8.000000e-09
GCST007560_7	Sleep duration (long sleep)	2.000000e-08
GCST007565_108	Morning person	9.000000e-22
GCST007565_113	Morning person	1.000000e-14
GCST010219_1	Attention deficit hyperactivity disorder (inattention symptoms)	8.000000e-07
GCST010322_1	Levodopa wearing off effect (time symptoms uncontrolled) in Parkinson’s disease (response to zonisamide)	4.000000e-06
GCST010988_521	Adult body size	3.000000e-08
GCST010989_24	Body size at age 10	4.000000e-08
GCST012006_7	Intralaminar thalamic nuclei volume	4.000000e-14
GCST90000025_895	Appendicular lean mass	3.000000e-15
GCST90000047_1	Age at first sexual intercourse	4.000000e-10
GCST90002395_500	Mean platelet volume	6.000000e-42
GCST90002401_3	Platelet distribution width	1.000000e-28

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0005677	puberty onset measurement
EFO:0004314	forced expiratory volume
EFO:0000714	survival time
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0007984	platelet component distribution width
EFO:0009180	rosacea severity measurement
EFO:0006336	diastolic blood pressure
EFO:0007660	neuroticism measurement
EFO:0009589	worry measurement
EFO:0008328	chronotype measurement
EFO:0010747	response to levodopa
EFO:0010749	motor function measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0006935	thalamus volume
EFO:0004980	appendicular lean mass
EFO:0009749	age at first sexual intercourse measurement
EFO:0004309	platelet count
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Silicon Dioxide	increases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
Benzo(a)pyrene	affects methylation, decreases methylation	2
Aflatoxin B1	affects methylation, increases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, affects methylation, decreases methylation	1
trichostatin A	increases expression	1
beta-lapachone	increases expression, decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	affects expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects methylation, affects cotreatment, decreases methylation	1
PCI 5002	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, affects methylation, decreases methylation, increases methylation	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Arsenic	decreases methylation	1
Cadmium	decreases expression, decreases reaction	1
Cannabinoids	increases abundance, affects methylation	1
Cisplatin	affects expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide