SLC18A3

protein-coding

solute carrier family 18 member A3, the group of Solute carrier family 18

Gene summary

This gene is a member of the vesicular amine transporter family. The encoded transmembrane protein transports acetylcholine into secretory vesicles for release into the extracellular space. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase. This gene is located within the first intron of the choline acetyltransferase gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003055.3

Inheritance

ClinVar variants

P:6U:188B:112

Top phenotype

Myasthenic syndrome, congenital, 21, presynaptic

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr10:49,610,310-49,612,720

External References & Databases

Ensembl (ENSG00000187714)

Transcript & Mutation Effects

hg38 • Region Span ~2.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myasthenic syndrome 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014983

Submitter: Genomics England PanelApp

congenital myasthenic syndrome 21LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014983

Submitter: Ambry Genetics

congenital myasthenic syndrome 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014983

Submitter: PanelApp Australia

fetal akinesia deformation sequence 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100101

Submitter: Orphanet

congenital myasthenic syndrome 21STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014983

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital, 21, presynapticAR

Manifestation: Musculoskeletal

Intervention: Musculoskeletal

Rationale: Early diagnosis and management has been described as beneficial, as individuals have been reported as responding to medical management (with pyridostigmine)

Refs: 27590285

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC18A3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 230

Inborn genetic diseasesTotal: 92

Congenital myasthenic syndrome 21Total: 21

SLC18A3-related disorderTotal: 11

not specifiedTotal: 6

CHAT-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003055.3. 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			6 clinvar	99 clinvar	2 clinvar	107
missense		2 clinvar	179 clinvar	8 clinvar	3 clinvar	192
nonsense		2 clinvar				2
start loss			1 clinvar			1
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	0	6	188	107	5	306

Highest pathogenic variant AF is 0.00008345052

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003055.3	RefSeq	NP_003046.2	1	MANE Select
ENST00000374115.5	Ensembl	ENSP00000363229.3	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)
Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction)
Synaptic Vesicle Pathway
Vesicle-mediated transport

Biological Process

drug transmembrane transport
neurotransmitter secretion
organic cation transport
membrane organization
ammonium transmembrane transport

Molecular Function

acetylcholine transmembrane transporter activity

Cellular Component

plasma membrane
integral component of membrane
AP-1 adaptor complex
AP-2 adaptor complex
clathrin-coated vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374115
Coding exons: 1
Length: 2419
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.145	311	318	0.977	0.0000151	3292
Missense (PolyPhen)		112	131.78	0.84989		1433
Synonymous	-2.63	190	149	1.27	0.00000768	1236
Loss of Function	2.33	2	9.90	0.202	4.26e-7	108

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in acetylcholine transport into synaptic vesicles. {ECO:0000269|PubMed:8071310}.;

Intolerance Scores

LoFtool: 0.523
RVIS EVS: -0.75
RVIS percentile EVS: 13.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.571

Gene Damage Prediction

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