SYNGAP1
Homo sapiens
Gene Name: synaptic Ras GTPase activating protein 1
Aliases: MRD5; RASA1; RASA5; SYNGAP
Chromosome No: 6
Chromosome Band: 6p21.32
Genetic Category: Rare Single Gene variant-Syndromic-Multigenic CNV-Functional-Rare single gene variant/Functional
Aliases: MRD5; RASA1; RASA5; SYNGAP
Chromosome No: 6
Chromosome Band: 6p21.32
Genetic Category: Rare Single Gene variant-Syndromic-Multigenic CNV-Functional-Rare single gene variant/Functional
Summary Statistics:
ASD Reports: 101
Recent Reports: 20
Annotated variants: 238
Associated CNVs: 1
Evidence score: 5
ASD Reports: 101
Recent Reports: 20
Annotated variants: 238
Associated CNVs: 1
Evidence score: 5
| Associated Disorders: |
|
Relevance to Autism
Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as intellectual disability and epilepsy (PMIDs 19196676, 20531469, 21237447, 23020937). Multiple LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23161826, 23708187, 26989088, 27525107, 28554332, 28708303). De novo LoF variants in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886) and in ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SYNGAP1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in SYNGAP1 were identified in an ASD proband from a cohort of 200 Canadian ASD trio families in PMID 27525107 and in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in PMID 27824329. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SYNGAP1 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
A major component of the postsynaptic density (PSD)associated with NMDA receptors
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.
ASD
epilepsy
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
ASD, epilepsy/seizures
Support
Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability
ID
Support
Recurrent de novo mutations implicate novel genes underlying simplex autism risk.
ASD
Support
The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing
ASD
Support
Monogenic developmental and epileptic encephalopathies of infancy and childhood
ASD, DD, ID, epilepsy/seizures
Support
Mutations in HECW2 are associated with intellectual disability and epilepsy.
ASD, ID, epilepsy/seizures
Support
Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder
ASD
Support
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.
ID
Epilepsy, ASD
Support
Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and d...
DD/ID, epilepsy/seizures
ASD
Support
Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental traje...
ID, epilepsy/seizures, autistic features
Microcephaly, growth delay, behavioral problems, s
Support
Massively parallel reporter assays discover de novo exonic splicing mutants in paralogs of Autism genes
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons
Support
Diagnostic value of partial exome sequencing in developmental disorders.
DD, ID
Microcephaly
Support
Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing
Pediatric Acute-Onset Neuropsychiatric Syndrome (P
Support
Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern.
ID
Support
A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies
DD, ID, epilepsy/seizures
Support
Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ASD, ID, epilepsy/seizures
Support
Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population
DD
Support
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
ID
Support
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
ID, epilepsy/seizures
Support
Novel SYNGAP1 variant in a patient with intellectual disability and distinctive dysmorphisms.
ASD, DD, ID
Support
Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description
ID
ASD, epilepsy/seizures
Support
Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.
ID, epilepsy/seizures
ASD
Support
Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening
ASD
Support
Functional impact of global rare copy number variation in autism spectrum disorders.
ASD
Support
Characterization of intellectual disability and autism comorbidity through gene panel sequencing.
ID, ASD or autistic traits
Support
A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.
ID
Support
Rare variants in the outcome of social skills group training for autism
ASD
Support
Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...
DD, ID, ASD
MCA
Support
Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures
ASD, DD, ID, epilepsy/seizures
ADHD
Support
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.
ASD
Support
Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy
Epilepsy/seizures
DD, ID
Support
Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.
DD, ID, epilepsy/seizures
Support
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations
ASD, ID
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
ID
Support
Autosomal dominant intellectual developmental diso
ASD, epilepsy/seizures
Support
Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.
Epilepsy/seizures
ASD, cognitive impairment
Support
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
DD, ID
Stereotypy
Support
Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.
ASD
Support
Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability
ID
Marfanoid habitus
Support
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
DD, epilepsy/seizures
Support
Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
Support
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
ASD
Support
Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study
DD, epilepsy/seizures
Support
The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.
Epilepsy/seizures
DD
Support
Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Support
Autism spectrum disorder and comorbid neurodevelopmental disorders (ASD-NDDs): Clinical and genetic profile of a pediatric cohort
ASD
Epilepsy/seizures
Support
6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.
ID
Epilepsy
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.
Epilepsy/seizures
DD/ID
Support
Diagnostic yield of patients with undiagnosed intellectual disability
DD, ID
Support
Large-scale discovery of novel genetic causes of developmental disorders.
DD, epilepsy/seizures
Support
Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing
DD
Support
Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...
ID
Behavioral abnormalities
Support
New genes involved in Angelman syndrome-like: Expanding the genetic spectrum
DD, epilepsy/seizures
Stereotypy
Support
Diagnostic exome sequencing in persons with severe intellectual disability.
ID
Epilepsy, ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Highly Cited
A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.
Highly Cited
SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.
Highly Cited
SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons.
Highly Cited
Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.
Highly Cited
Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking.
Recent Recommendation
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
Epilepsy
ID, ASD, DD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.
ID
ASD, Epilepsy
Recent Recommendation
De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.
ID
ASD, epilepsy/seizures
Recent Recommendation
Autosomal dominant intellectual developmental diso
DD, ID, epilepsy/seizures
Recent Recommendation
Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.
Recent Recommendation
Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption...
Recent Recommendation
Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
ID
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Recent Recommendation
Multi-parametric analysis of 57 SYNGAP1 variants reveal impacts on GTPase signaling, localization, and protein stability
ASD, ID
Recent Recommendation
A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation.
ID
Recent Recommendation
SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks.
Recent Recommendation
SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.
Epilepsy/seizures, DD, ID
ASD
Recent Recommendation
Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP.
Recent Recommendation
SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity.
Recent Recommendation
SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits.
Recent Recommendation
Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
ID
Rare
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
GEN245R011
frameshift_variant
c.322_326del
p.Lys108CysfsTer42
De novo
Simplex
GEN245R014
frameshift_variant
c.1253_1254del
p.Lys418ArgfsTer54
De novo
Simplex
GEN245R016
frameshift_variant
c.283dup
p.His95ProfsTer5
Familial
Paternal
Simplex
GEN245R027
frameshift_variant
c.1821_1822del
p.Phe608TrpfsTer9
De novo
Simplex
GEN245R029
frameshift_variant
c.1781del
p.Phe594SerfsTer56
De novo
Simplex
GEN245R030
frameshift_variant
c.3682_3685del
p.Glu1228LysfsTer6
De novo
Simplex
GEN245R034
missense_variant
c.2627G>C
p.Arg876Pro
Familial
Maternal
Simplex
GEN245R035
missense_variant
c.310C>T
p.Arg104Cys
Familial
Maternal
Simplex
GEN245R036
missense_variant
c.1465C>T
p.Leu489Phe
Familial
Paternal
Simplex
GEN245R037
missense_variant
c.3445C>T
p.Pro1149Ser
Familial
Maternal
Simplex
GEN245R041
stop_gained
c.3235C>T
p.Gln1079Ter
De novo
Multi-generational
GEN245R042
stop_gained
c.2740C>T
p.Gln914Ter
De novo
Simplex
GEN245R043
frameshift_variant
c.1552_1555del
p.Tyr518AsnfsTer8
De novo
Simplex
GEN245R044
frameshift_variant
c.431_434del
p.Thr144SerfsTer29
De novo
Simplex
GEN245R045
frameshift_variant
c.2690del
p.Val897AlafsTer166
De novo
Multiplex
GEN245R046
missense_variant
c.509G>A
p.Arg170Gln
De novo
Multi-generational
GEN245R047
stop_gained
c.2722C>T
p.Gln908Ter
De novo
Simplex
GEN245R050
missense_variant
c.980T>C
p.Leu327Pro
De novo
Multiplex (monozygotic twins)
GEN245R058
frameshift_variant
c.455_459del
p.Arg152GlnfsTer14
De novo
Simplex
GEN245R066
frameshift_variant
c.2214_2217del
p.Glu739GlyfsTer20
De novo
Simplex
GEN245R073a
frameshift_variant
c.1670_1671insA
p.His558ProfsTer60
De novo
Simplex
GEN245R075
frameshift_variant
c.3545del
p.Glu1182GlyfsTer14
Unknown
Not maternal
GEN245R078
frameshift_variant
c.1043_1044del
p.Val348AlafsTer70
De novo
Simplex
GEN245R094
frameshift_variant
c.254_255del
p.Thr85SerfsTer14
De novo
Simplex
GEN245R095
frameshift_variant
c.333del
p.Lys114SerfsTer20
De novo
Simplex
GEN245R096
frameshift_variant
c.424_427del
p.Lys142GlufsTer31
De novo
Simplex
GEN245R098
frameshift_variant
c.435_447dup
p.Leu150ValfsTer6
De novo
Multiplex
GEN245R101
frameshift_variant
c.690dup
p.Phe231LeufsTer14
De novo
Simplex
GEN245R103
frameshift_variant
c.1167_1168del
p.Gly391GlnfsTer27
De novo
Extended multiplex
GEN245R105
frameshift_variant
c.1393del
p.Leu465PhefsTer9
De novo
Simplex
GEN245R106
frameshift_variant
c.1463del
p.Thr488SerfsTer7
De novo
Extended multiplex
GEN245R108
frameshift_variant
c.1726_1728delinsGGCT
p.Cys576GlyfsTer42
De novo
Simplex
GEN245R113
frameshift_variant
c.2177_2180del
p.Arg726ThrfsTer33
De novo
Simplex
GEN245R116
frameshift_variant
c.2936_2938delinsCA
p.Phe979SerfsTer98
De novo
Extended multiplex
GEN245R117
frameshift_variant
c.3364dup
p.Gln1122ProfsTer17
De novo
Extended multiplex
GEN245R126
missense_variant
c.968T>C
p.Leu323Pro
De novo
Extended multiplex
GEN245R128
missense_variant
c.1210G>C
p.Ala404Pro
De novo
Extended multiplex
GEN245R130
inframe_deletion
c.1388_1393del
p.Asp463_Leu465delinsVal
De novo
Simplex
GEN245R131
inframe_insertion
c.1392_1394dup
p.Leu465dup
De novo
Extended multiplex
GEN245R137
missense_variant
c.121C>T
p.Arg41Cys
Unknown
Extended multiplex
GEN245R139
missense_variant
c.877C>T
p.Arg293Cys
Unknown
Not maternal
Simplex
GEN245R150
frameshift_variant
c.1154_1161del
p.Ser385TrpfsTer31
Unknown
GEN245R151
frameshift_variant
c.1167_1168del
p.Gly391GlnfsTer27
Unknown
GEN245R154
frameshift_variant
c.3233_3236del
p.Val1078AlafsTer51
Unknown
GEN245R155
frameshift_variant
c.2520_2536del
p.Leu841PhefsTer77
Unknown
GEN245R165
stop_gained
c.2590_2591insTTAGTGTGTTGGTTAGTAGGCCTAGTATGAGGAGCGTTATGGAGTGGAAGTGAAATCACATGGCTACCTGG
p.Ala864ValfsTer18
De novo
Simplex
GEN245R167
frameshift_variant
c.2145_2146dup
p.Arg716ProfsTer11
De novo
Simplex
GEN245R174
missense_variant
ENSG00000197283:ENST00000293748:exon15:c.G2444A:p.R815H,ENSG00000197283:ENST00000449372:exon14:c.G24
De novo
GEN245R179
frameshift_variant
c.1167_1168del
p.Gly391GlnfsTer27
De novo
Simplex
GEN245R227
frameshift_variant
c.3466_3467del
p.Ser1156CysfsTer19
Unknown
Simplex
Common
No Common Variants Available
