GeneBe

SLC18A2

protein-coding

solute carrier family 18 member A2, the group of Solute carrier family 18

Gene summary

This gene encodes an transmembrane protein that functions as an ATP-dependent transporter of monoamines, such as dopamine, norepinephrine, serotonin, and histamine. This protein transports amine neurotransmitters into synaptic vesicles. Polymorphisms in this gene may be associated with schizophrenia, bipolar disorder, and other neurological/psychiatric ailments. [provided by RefSeq, Jun 2018]

Previous symbols:
  • VMAT2

MANE transcript

NM_003054.6

Inheritance

AR

ClinVar variants

P:15U:100B:66

Top phenotype

Parkinsonism-dystonia, infantile, 2

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr10:117,241,093-117,279,430

External References & Databases

Ensembl (ENSG00000165646)NCBI Gene (6571)OMIM (193001)HGNC:10935GenCCUniProt (Q05940)AlphaFoldClinVar (SLC18A2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~38.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

brain dopamine-serotonin vesicular transport diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018130

Submitter: Orphanet

brain dopamine-serotonin vesicular transport diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018130

Submitter: ClinGen

The SLC18A2 gene, coding for the vesicular monoamine transporter 2 (VMAT2), plays a crucial role in transporting monoamine neurotransmitters into synaptic vesicles. SLC18A2 was first reported in relation to autosomal recessive brain dopamine-serotonin vesicular transport disease in 2013 (Rilstone et al., PMID: 23363473). The affected individuals typically present global developmental delay and cognitive impairment, hypotonia, dystonia and Parkinsonism, oculogyric crisis, temperature dysregulation, excessive sweating, hypersalivation, and gastrointestinal dysmotility with inter- and intra-familial variability. Twenty-two unique variants, including missense, nonsense, and frameshift variants, have been reported in 25 affected individuals in 9 publications (PMIDs: 23363473, 31240161, 28716265, 26497564, 29450879, 26539891, 36318270, 31618753, 3871642) and are 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 is known to be loss-of-function. This gene-disease association is also supported by experimental evidence. Overexpression of SLC18A2 Pro387Leu mutant in COS-7 cells dramatically decreased monoamine uptake without affecting protein glycosylation (PMID: 23363473). Platelets derived from the patient with SLC18A2 Pro316Ala alteration showed significantly lower serotonin levels, abnormal morphology, and reduced aggregation response in comparison to the heterozygous carriers and controls (PMID: 31240161). Homozygous knockout (KO) mice exhibited various symptoms including small size, poor suckling, hypoactivity, motor coordination issues, and neonatal death (PMID: 9427250, 9427251, 11463816). Additionally, a transgenic mouse line expressing ~5% normal VMAT2 levels [low expressor VMAT2 LO] led to age-dependent reduction in dopamine content and uptake in brain, abnormal locomotor skills and neuronal degeneration similar to Parkinson disease (PMID: 17652604). These features are consistent with the symptoms presented by patients harboring SLC18A2 variants. SLC18A2-overexpressing mice using a bacterial artificial chromosome (BAC) showed increased vesicular volume, dopamine uptake, content and release, along with increased locomotor activity, and reduced anxiety/depressive behavior (PMID: 24979780). In summary, SLC18A2 is definitively associated with autosomal recessive brain dopamine-serotonin vesicular transport disease. 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 IEM GCEP on the meeting date July 26, 2024] (SOP Version 10).

brain dopamine-serotonin vesicular transport diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018130

Submitter: G2P

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

parkinsonism-dystonia, infantile, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054836

Submitter: Labcorp Genetics (formerly Invitae)

parkinsonism-dystonia, infantile, 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0054836

Submitter: Ambry Genetics

brain dopamine-serotonin vesicular transport diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018130

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Parkinsonism-dystonia, infantile, 2AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: The condition can manifest with neurologic manifestations such as movement disorders and autonomic dysfunctiontreatment, and medical management with a dopamine receptor agonist has been described as resulting in marked clinical improvement

Refs: 23363473Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC18A2 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 171
Inborn genetic diseasesTotal: 54
Brain dopamine-serotonin vesicular transport diseaseTotal: 14
not specifiedTotal: 6
SLC18A2-related disorderTotal: 6
Abnormal dense granule contentTotal: 1
Abnormal dense granulesTotal: 1
Abnormal brain morphologyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003054.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
61
clinvar
 63
missense
5
clinvar
94
clinvar
3
clinvar
2
clinvar
 104
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
5
clinvar
1
clinvar
1
clinvar
 7
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
1
clinvar
 4
Total78100642181

Highest pathogenic variant AF is 0.00003779233

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003054.6RefSeqNP_003045.215MANE Select
ENST00000644641.2EnsemblENSP00000496339.115MANE Select
ENST00000853677.1EnsemblENSP00000523736.116Standard
ENST00000853677.2EnsemblENSP00000523736.116Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
slc18a2Danio rerio

Structure: brain

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Synaptic vesicle cycle - Homo sapiens (human)
  • Serotonergic synapse - Homo sapiens (human)
  • Dopaminergic synapse - Homo sapiens (human)
  • Amphetamine addiction - Homo sapiens (human)
  • Parkinson,s disease - Homo sapiens (human)

Biological Process

  • response to amphetamine
  • neurotransmitter transport
  • chemical synaptic transmission
  • neurotransmitter secretion
  • locomotory behavior

Molecular Function

  • serotonin:sodium symporter activity
  • monoamine transmembrane transporter activity

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • synaptic vesicle
  • membrane
  • synaptic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000298472
Coding exons
15
Length
38338
Individuals with no LoFs
125704
Homozygous LoFs
0
Heterozygous LoFs
44
Defined
125748
p
0.000175
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.252403010.7970.00001643353
Missense (PolyPhen)3562.5690.55938653
Synonymous-0.02531221221.000.000008041023
Loss of Function3.42725.70.2720.00000124297

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000350.00035rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.0000540.000054rare
Finnish0.000280.00028rare
European (Non-Finnish)0.000130.00013rare
South Asian0.000230.00023rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Requisite for vesicular amine storage prior to secretion via exocytosis.;

Recessive Scores

pRec
0.214

Intolerance Scores

LoFtool
0.354
RVIS EVS
-0.71
RVIS percentile EVS
14.4

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.194

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.