CAMTA1

protein-coding

calmodulin binding transcription activator 1, the group of Calmodulin binding transcription activators |IPT domain containing

Gene summary

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. [provided by RefSeq, Mar 2017]

MANE transcript

NM_015215.4

Inheritance

ClinVar variants

P:110U:517B:264

Top phenotype

Cerebellar ataxia, nonprogressive, with mental retardation

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr1:6,785,454-7,769,706

External References & Databases

Ensembl (ENSG00000171735)

Transcript & Mutation Effects

hg38 • Region Span ~984.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar dysfunction with variable cognitive and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013886

Submitter: Ambry Genetics

cerebellar dysfunction with variable cognitive and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013886

Submitter: G2P

cerebellar dysfunction with variable cognitive and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013886

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar dysfunction with variable cognitive and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013886

Submitter: ClinGen

*CAMTA1* was first reported in relation to cerebellar dysfunction with variable cognitive & behavioral abnormalities in 2011 (Mikhail et.al, PMID: 22031302). Probands are characterized by cerebellar ataxia, global developmental delay, speech delay, hypotonia, dysmorphism, behavioral abnormalities (ADHD, OCD, autistic features) and movement disorders such as tremors and myotonic dystonia. Less common phenotypes include epilepsy, GERD, velopharyngeal insufficiency, constipation, strabismus & nystagmus. Inheritance of variants is primarily de novo. Twenty one variants (missense, nonsense, frameshift, CNV: deletions & duplications) in 22 probands in 7 publications (PMIDs: 22031302, 33131045, 33677721, 30838254, 22693284, 24738973, 32157189) have been included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be haploinsufficiency, but a dominant negative mechanism could not be ruled out (PMID:22693284). This gene-disease relationship is also supported by experimental evidence..Both constitutive deletion of *Camta1* and conditional deletion in the G nervous system causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy in mice, partially recapitulating the consequences of haploinsufficiency of the human *CAMTA1* locus (PMID: 25049392). In summary, there is definitive evidence to support the relationship between *CAMTA1* and cerebellar dysfunction with variable cognitive and behavioral abnormalities. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 16, 2023 (SOP 9).

cerebellar dysfunction with variable cognitive and behavioral abnormalitiesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013886

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cerebellar ataxia, nonprogressive, with mental retardationAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22693284

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAMTA1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 667

Inborn genetic diseasesTotal: 201

Cerebellar dysfunction with variable cognitive and behavioral abnormalitiesTotal: 171

not specifiedTotal: 99

CAMTA1-related disorderTotal: 73

Intellectual disabilityTotal: 10

See casesTotal: 4

Neurodevelopmental abnormalityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015215.4. Only rare variants are included.

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

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

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	7 clinvar	168 clinvar	11 clinvar	187
missense	1 clinvar	11 clinvar	498 clinvar	80 clinvar	5 clinvar	595
nonsense	14 clinvar	22 clinvar	5 clinvar			41
start loss			1 clinvar			1
frameshift	34 clinvar	13 clinvar	2 clinvar			49
splice donor/acceptor (+/-2bp)	1 clinvar	13 clinvar	4 clinvar			18
Total	50	60	517	248	16	891

Highest pathogenic variant AF is 0.000008227157

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 105 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015215.4	RefSeq	NP_056030.1	23	MANE Select
ENST00000303635.12	Ensembl	ENSP00000306522.6	23	MANE Select
NM_001195563.2	RefSeq	NP_001182492.1	4	Standard
NM_001242701.2	RefSeq	NP_001229630.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in muscle cell - TarBase

Biological Process

positive regulation of protein dephosphorylation
positive regulation of transcription by RNA polymerase II
neuromuscular process controlling balance
positive regulation of calcineurin-NFAT signaling cascade

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
sequence-specific DNA binding

Cellular Component

nucleus
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303635
Coding exons: 23
Length: 984383
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.26	725	1.02e+3	0.712	0.0000652	11017
Missense (PolyPhen)		302	480.25	0.62884		5301
Synonymous	0.711	417	436	0.957	0.0000326	3288
Loss of Function	7.37	7	76.6	0.0913	0.00000413	835

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00025	0.00023	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator. May act as a tumor suppressor. {ECO:0000269|PubMed:11925432, ECO:0000269|PubMed:15709179}.;
Disease: DISEASE: Cerebellar ataxia, non-progressive, with mental retardation (CANPMR) [MIM:614756]: A 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. {ECO:0000269|PubMed:22693284}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.00455
RVIS EVS: -2.13
RVIS percentile EVS: 1.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.705

Gene Damage Prediction

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