SYN1

protein-coding

synapsin I, the group of Synapsins

Gene summary

This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

Previous symbols:

MRX50

MANE transcript

NM_006950.3

Inheritance

ClinVar variants

P:75U:304B:196

Top phenotype

Epilepsy, X-linked, with variable learning disabilities and behavior disorders; Intellectual developmental disorder, X-linked 50

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chrX:47,571,901-47,619,857

External References & Databases

Ensembl (ENSG00000008056)

Transcript & Mutation Effects

hg38 • Region Span ~48.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsy, X-linked 1, with variable learning disabilities and behavior disordersSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010339

Submitter: Labcorp Genetics (formerly Invitae)

epilepsy, X-linked 1, with variable learning disabilities and behavior disordersMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010339

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*SYN1* was first reported in relation to X-linked complex neurodevelopmental disorder in 2004 (Garcia *et al*., PMID: 14985377). To date, more than 40 *SYN1* variants, mostly truncating, have been reported in individuals with variable neurodevelopmental phenotypes, including behavioral disturbances such as autism spectrum disorder or attention deficit-hyperactivity disorder (91%), epilepsy (82%), intellectual disability (77%), and developmental delay (70%) (PMID: 36568968). Reflex epilepsy, including bathing epilepsy, is characteristic of *SYN1*-related disorder. *SYN1* variants co-segregating with disease have been reported in several large families (PMIDs: 14985377, 21441247, 28973667, 36568968). *SYN1* variants predominantly affect males, while females exhibit a wider clinical heterogeneity and incomplete penetrance. This gene-disease relationship is also supported by experimental evidence. *SYN1* encodes synapsin 1, a presynaptic phosphoprotein involved in synaptic development, function, and plasticity. *Syn1* knock-out mice exhibit enhanced stimulation-evoked epileptic seizures and autism-related behavioral abnormalities (PMIDs: 7568107, 7568108, 23280234). Overexpression of *SYN1* nonsense variants in hippocampal neurons from *Syn1* knock-out mice result in impaired axon elongation, disrupted synaptic vesicle pools, and formation of perinuclear aggregates (PMIDs: 21441247, 23818987). In summary, there is definitive evidence supporting the relationship between *SYN1* and X-linked complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2023 (SOP Version 9). This gene-disease relationship was originally evaluated on December 5, 2018 and given a Moderate classification. Curation of additional genetic evidence resulted in the classification being updated.

epilepsy, X-linked 1, with variable learning disabilities and behavior disordersSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010339

Submitter: G2P

epilepsy, X-linked 1, with variable learning disabilities and behavior disordersSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010339

Submitter: Orphanet

epilepsy, X-linked 1, with variable learning disabilities and behavior disordersMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010339

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 50STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010251

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Epilepsy, X-linked, with variable learning disabilities and behavior disorders; Intellectual developmental disorder, X-linked 50XL

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: 14985377; 28973667

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYN1 variants in ClinVar

15 Conditions Cataloged

Epilepsy, X-linked 1, with variable learning disabilities and behavior disordersTotal: 495

not providedTotal: 186

not specifiedTotal: 92

Inborn genetic diseasesTotal: 88

SYN1-related disorderTotal: 34

Intellectual disability, X-linked 50Total: 19

History of neurodevelopmental disorderTotal: 6

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006950.3. 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		1 clinvar	14 clinvar	163 clinvar	4 clinvar	182
missense	1 clinvar	4 clinvar	285 clinvar	27 clinvar	2 clinvar	319
nonsense	11 clinvar	4 clinvar	1 clinvar			16
start loss		1 clinvar	1 clinvar			2
frameshift	31 clinvar	12 clinvar	1 clinvar			44
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	2 clinvar			12
Total	45	30	304	190	6	575

Highest pathogenic variant AF is 0.0000063585053

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006950.3	RefSeq	NP_008881.2	13	MANE Select
ENST00000295987.13	Ensembl	ENSP00000295987.7	13	MANE Select
NM_133499.2	RefSeq	NP_598006.1	13	Standard
ENST00000340666.5	Ensembl	ENSP00000343206.4	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic Vesicle Pathway
Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
Monoamine Transport
Neuronal System
Dopamine Neurotransmitter Release Cycle

Biological Process

chemical synaptic transmission
neurotransmitter secretion
regulation of neurotransmitter secretion
neuron development
synapse organization

Molecular Function

actin binding
transporter activity
protein binding
ATP binding
protein kinase binding

Cellular Component

synaptonemal complex
Golgi apparatus
cytosol
cytoskeleton
synaptic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295987
Coding exons: 13
Length: 47950
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	2.97	116	247	0.469	0.0000196	4477
Missense (PolyPhen)		17	57.239	0.297		1005
Synonymous	1.44	91	110	0.826	0.00000964	1513
Loss of Function	3.82	1	18.9	0.0529	0.00000133	320

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: Neuronal phosphoprotein that coats synaptic vesicles, binds to the cytoskeleton, and is believed to function in the regulation of neurotransmitter release. The complex formed with NOS1 and CAPON proteins is necessary for specific nitric-oxid functions at a presynaptic level.;
Disease: DISEASE: Epilepsy X-linked, with variable learning disabilities and behavior disorders (XELBD) [MIM:300491]: A neurologic disorder characterized by variable combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behavior. {ECO:0000269|PubMed:14985377}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.628

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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