SYT1

protein-coding

synaptotagmin 1, the group of Synaptotagmins|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the synaptotagmin protein family. The synaptotagmins are integral membrane proteins of synaptic vesicles that serve as calcium sensors in the process of vesicular trafficking and exocytosis. The encoded protein participates in triggering neurotransmitter release at the synapse in response to calcium binding. Mutations in this gene are associated with Baker-Gordon syndrome. [provided by RefSeq, Jan 2023]

Previous symbols:

SYT
SVP65

MANE transcript

NM_005639.3

Inheritance

ClinVar variants

P:24U:80B:20

Top phenotype

Baker-Gordon syndrome

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr12:78,863,993-79,452,008

External References & Databases

Ensembl (ENSG00000067715)

Transcript & Mutation Effects

hg38 • Region Span ~588.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033864

Submitter: Ambry Genetics

infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033864

Submitter: Illumina

The SYT1 gene was first reported in relation to autosomal dominant SYT1-associated neurodevelopmental disorder in 2018 (30107533: Baker et al. 2018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least five unique missense variants have been reported in a total of 11 cases, all from a single study (30107533: Baker et al. 2018). All the reported variants were de novo. The mechanism for disease is unknown. This gene-disease relationship is supported by in vitro functional assays and expression data (22031440: Kang et al. 2011; 30107533: Baker et al. 2018). The biochemical function of the protein is well-described, but the mechanism of disease is not entirely clear. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033864

Submitter: Labcorp Genetics (formerly Invitae)

infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033864

Submitter: G2P

infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033864

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Baker-Gordon syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 25705886; 30107533

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYT1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 56

Inborn genetic diseasesTotal: 30

Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndromeTotal: 29

SYT1-related disorderTotal: 14

not specifiedTotal: 11

SYT1-associated neurodevelopmental disorderTotal: 6

Neurodevelopmental disorderTotal: 1

Syndromic intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005639.3. 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				16 clinvar	1 clinvar	17
missense	3 clinvar	19 clinvar	71 clinvar	3 clinvar		96
nonsense	1 clinvar		4 clinvar			5
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	4	20	80	19	1	124

Highest pathogenic variant AF is 0.0000013681575

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 97 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005639.3	RefSeq	NP_005630.1	8	MANE Select
ENST00000261205.9	Ensembl	ENSP00000261205.4	8	MANE Select
NM_001135805.2	RefSeq	NP_001129277.1	8	Standard
NM_001135806.2	RefSeq	NP_001129278.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Synaptic Vesicle Pathway
Disease
Vesicle-mediated transport
Membrane Trafficking

Biological Process

detection of calcium ion
chemical synaptic transmission
neurotransmitter secretion
brain development
glutamate secretion

Molecular Function

SNARE binding
phosphatidylserine binding
calcium ion binding
protein binding
calmodulin binding

Cellular Component

cytoplasm
Golgi apparatus
plasma membrane
synaptic vesicle
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261205
Coding exons: 8
Length: 588016
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125747
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.84	109	230	0.474	0.0000118	2791
Missense (PolyPhen)		11	73.827	0.149		918
Synonymous	0.229	89	91.8	0.970	0.00000536	780
Loss of Function	3.35	4	20.3	0.197	0.00000111	253

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000269|PubMed:23999003}.;
Disease: DISEASE: Note=A SYT1 rare mutation has been found in a child with a severe neuro-developmental disorder. The individual harboring this variant shows early onset dyskinetic movement disorder, severe motor delay and profound cognitive impairment, suggesting that SYT1 may play a role in the pathogenesis of this neuro- developmental disorder. {ECO:0000269|PubMed:25705886}.;

Recessive Scores

pRec: 0.466

Intolerance Scores

LoFtool: 0.484
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.786

Gene Damage Prediction

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