VAMP1

protein-coding

vesicle associated membrane protein 1, the group of Vesicle associated membrane proteins

Gene summary

Synapotobrevins, syntaxins, and the synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]

Previous symbols:

SYB1

MANE transcript

NM_014231.5

Inheritance

AD, AR

ClinVar variants

P:15U:46B:17

Top phenotype

Myasthenic syndrome, congenital, 25, presynaptic

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr12:6,462,237-6,470,677

External References & Databases

Ensembl (ENSG00000139190)

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic ataxia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007164

Submitter: Labcorp Genetics (formerly Invitae)

presynaptic congenital myasthenic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020345

Submitter: Orphanet

spastic ataxia 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007164

Submitter: Orphanet

spastic ataxia 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007164

Submitter: PanelApp Australia

myasthenic syndrome, congenital, 25, presynapticSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032675

Submitter: Genomics England PanelApp

myasthenic syndrome, congenital, 25, presynapticSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032675

Submitter: Labcorp Genetics (formerly Invitae)

myasthenic syndrome, congenital, 25, presynapticSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032675

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital, 25, presynapticAR

Manifestation: Musculoskeletal; Neurologic

Intervention: Musculoskeletal; Neurologic

Rationale: The condition can involve neonatal hypotonia and generalized muscle weakness, and medicial management (with pyridostigmine) has been described as beneficial

Refs: 11774073; 22958904; 28168212; 28253535; 28600779

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VAMP1 variants in ClinVar

9 Conditions Cataloged

Spastic paraplegiaTotal: 98

not providedTotal: 27

Myasthenic syndrome, congenital, 25, presynapticTotal: 10

Inborn genetic diseasesTotal: 7

Spastic ataxia 1Total: 5

VAMP1-related disorderTotal: 2

Houge-Janssens syndrome 2Total: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014231.5. 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	17 clinvar		18
missense			40 clinvar			40
nonsense	1 clinvar	3 clinvar				4
start loss						0
frameshift	3 clinvar	4 clinvar	2 clinvar			9
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	3 clinvar			7
Total	6	9	46	17	0	78

Highest pathogenic variant AF is 0.000015489852

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014231.5	RefSeq	NP_055046.1	5	MANE Select
ENST00000396308.4	Ensembl	ENSP00000379602.3	5	MANE Select
NM_001297438.2	RefSeq	NP_001284367.1	5	Standard
NM_016830.4	RefSeq	NP_058439.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

SNARE interactions in vesicular transport - Homo sapiens (human)
Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
Disease
Toxicity of botulinum toxin type D (BoNT/D)
Toxicity of botulinum toxin type F (BoNT/F)

Biological Process

synaptic vesicle priming
regulation of synaptic vesicle fusion to presynaptic active zone membrane
SNARE complex assembly

Molecular Function

protein binding

Cellular Component

mitochondrial outer membrane
cytosol
integral component of plasma membrane
cell surface
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396308
Coding exons: 5
Length: 8751
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.23	38	66.3	0.573	0.00000332	764
Missense (PolyPhen)		10	16.869	0.5928		222
Synonymous	0.471	20	22.9	0.875	0.00000112	233
Loss of Function	1.28	5	9.18	0.545	5.76e-7	87

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the targeting and/or fusion of transport vesicles to their target membrane.;
Disease: DISEASE: Spastic ataxia 1, autosomal dominant (SPAX1) [MIM:108600]: An autosomal dominant form of spastic ataxia, a progressive neurodegenerative disorder characterized by lower-limb spasticity and generalized ataxia with dysarthria, impaired ocular movements, and gait disturbance. {ECO:0000269|PubMed:22958904}. Note=The disease is caused by mutations affecting the gene represented in this entry. A mutation affecting a critical donor site for the splicing of VAMP1 isoforms leads to the loss of neuron-specific isoform 1 and subsequently results in haploinsufficiency (PubMed:22958904). Therefore, there would be less neurotransmitter exocytosis in specific regions of the brain, causing the symptoms of SPAX1. {ECO:0000303|PubMed:22958904}.;

Recessive Scores

pRec: 0.137

Intolerance Scores

RVIS EVS: 0.24
RVIS percentile EVS: 68.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.815

Gene Damage Prediction

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