Human Gene Module / Chromosome 6 / SYNGAP1

SYNGAP1synaptic Ras GTPase activating protein 1

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
10 / 39
Rare Variants / Common Variants
83 / 0
Aliases
SYNGAP1, MRD5,  RASA1,  RASA5,  SYNGAP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
6p21.32
Associated Disorders
DD/NDD, EP, EPS, ID, ASD
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.

Molecular Function

A major component of the postsynaptic density (PSD)associated with NMDA receptors

Reports related to SYNGAP1 (39 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Kim MJ , et al. (2005) No -
2 Highly Cited Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Flavell SW , et al. (2006) No -
3 Highly Cited SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Rumbaugh G , et al. (2006) No -
4 Recent Recommendation Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. Hamdan FF , et al. (2009) No -
5 Recent Recommendation Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. Muhia M , et al. (2010) No -
6 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
7 Recent Recommendation A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Krepischi AC , et al. (2010) No -
8 Support A de novo paradigm for mental retardation. Vissers LE , et al. (2010) No -
9 Primary De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Hamdan FF , et al. (2011) Yes epilepsy
10 Recent Recommendation Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Hamdan FF , et al. (2011) No -
11 Recent Recommendation Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. Lee KJ , et al. (2011) No -
12 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No Epilepsy, ASD
13 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
14 Recent Recommendation Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Berryer MH , et al. (2012) No ASD, Epilepsy
15 Support 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. Writzl K and Knegt AC (2013) No Epilepsy
16 Recent Recommendation Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
17 Recent Recommendation SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity. Clement JP , et al. (2013) No -
18 Support Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Willsey AJ , et al. (2013) Yes -
19 Recent Recommendation SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. Wang CC , et al. (2014) No -
20 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
21 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
22 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
23 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
24 Recent recommendation Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruption... Kozol RA , et al. (2015) No -
25 Recent recommendation De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Parker MJ , et al. (2015) No ASD, epilepsy/seizures
26 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
27 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
28 Support Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Mignot C , et al. (2016) No ASD (8/16 cases)
29 Support Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern. Fieremans N , et al. (2016) No -
30 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) Yes -
31 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
32 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
33 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No ASD and cognitive impairment (1/2 cases)
34 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
35 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
36 Support Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental traje... Prchalova D , et al. (2017) No Microcephaly, growth delay, behavioral problems, s
37 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No ASD and epilepsy/seizures (1/2 cases)
38 Highly Cited SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Kim JH , et al. (1998) No -
39 Highly Cited A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Chen HJ , et al. (1998) No -
Rare Variants   (83)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.412A>T p.Lys138Ter stop_gained De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.1735C>T p.Arg579Ter stop_gained De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.2438delT p.Leu813Argfs frameshift_variant De novo - Simplex 19196676 Hamdan FF , et al. (2009)
c.3344T>C p.Ile1115Thr missense_variant Unknown - Unknown 19196676 Hamdan FF , et al. (2009)
- - copy_number_loss De novo - - 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - Simplex 20683986 Krepischi AC , et al. (2010)
c.998_999del p.Val333AlafsTer frameshift_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.2677delC p.Gln893Ter frameshift_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
GAAGdel321-324 p.Lys108Ter frameshift_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
c.2294+1G>A - splice_site_variant De novo - Simplex 21237447 Hamdan FF , et al. (2011)
c.412A>T p.Lys138Ter stop_gained De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.1735C>T p.Arg579Ter stop_gained De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.2438delT p.Leu813Argfs frameshift_variant De novo - Simplex 21376300 Hamdan FF , et al. (2011)
c.2630dup p.Thr878AspfsTer60 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.1253_1254del p.Lys418ArgfsTer54 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.510-1G>A - splice_site_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.283dupC p.His95ProfsTer5 frameshift_variant Familial Paternal Simplex 23161826 Berryer MH , et al. (2012)
c.1084T>C p.Trp362Arg missense_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.1685C>T p.Pro562Leu missense_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.2212_2213del p.Ser738Ter frameshift_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
c.2184delC p.Asn729ThrfsTer31 frameshift_variant De novo - Simplex 23161826 Berryer MH , et al. (2012)
- - copy_number_loss Apparently de novo - Simplex 23687080 Writzl K and Knegt AC (2013)
- p.Trp267Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
c.427C>T p.Arg143Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
- p.Lys108ValfsTer25 frameshift_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.389-2A>T - splice_site_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.2104C>T p.Gln702Ter stop_gained Unknown - - 23708187 Carvill GL , et al. (2013)
delTT - frameshift_variant De novo - Simplex 24267886 Willsey AJ , et al. (2013)
c.3134C>G p.Ala1045Gly missense_variant Unknown Not tested - 24690944 Brett M , et al. (2014)
c.3583-6G>A p.Val1195AlafsTer27 splice_site_variant De novo - Simplex 25167861 Redin C , et al. (2014)
delC - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3682_3685del p.Glu1228fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1081C>T p.Gln361Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2899C>T p.Arg967Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.140G>A p.Arg47Gln missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2492G>C p.Arg831Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.310C>T p.Arg104Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1288C>T p.Leu430Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3445C>T p.Arg1149Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.425A>T p.Lys142Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.423G>C p.Leu141Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2444G>A p.Arg815His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3055C>T p.Arg1019Cys missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.698G>A p.Cys233Tyr missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3235C>T p.Gln1079Ter stop_gained De novo - Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.2740C>T p.Gln928Ter (p.Gln914Ter) stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1550_1555delTGTATGinsTG p.Tyr518AsnfsTer8 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.425_434delAACGAACGAAinsAACGAA p.Thr144SerfsTer29 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2732delT p.Leu925Ter (p.Leu911ProfsTer152) frameshift_variant De novo - Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
c.509G>A p.Arg170Gln missense_variant De novo - Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
c.2722C>T p.Arg922Ter (p.Arg908Ter) stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - Simplex 26079862 Parker MJ , et al. (2015)
c.1081T>C p.Leu327Pro missense_variant De novo - Multiplex (monozygotic twins) 26079862 Parker MJ , et al. (2015)
c.829dupC p.Pro277ProfsTer7 frameshift_variant De novo - - 26544041 Zhang Y , et al. (2015)
c.68-1518-?_1530_?del p.? copy_number_loss De novo - Simplex 26989088 Mignot C , et al. (2016)
c.348C>A p.Tyr116Ter stop_gained De novo - Extended multiplex 26989088 Mignot C , et al. (2016)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.427C>T p.Arg143Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.455_459del p.Arg152GlnfsTer14 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.490C>T p.Arg164Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.509+1G>T p.? splice_site_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.828dup p.Lys277GlnfsTer7 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.1057delC p.Leu353TrpfsTer13 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.1630C>T p.Arg544Ter stop_gained De novo - Simplex 26989088 Mignot C , et al. (2016)
c.1685C>T p.Pro562Leu missense_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.1995T>A p.Tyr665Ter stop_gained Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.2214_2217del p.Glu739GlyfsTer20 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.2933del p.Pro978HisfsTer99 frameshift_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.3406dup p.Gln1136ProfsTer17 frameshift_variant Unknown - Simplex 26989088 Mignot C , et al. (2016)
c.3408+1G>A p.? splice_site_variant De novo - Simplex 26989088 Mignot C , et al. (2016)
c.3494C>T p.Ser1165Leu missense_variant Unknown - - 27159028 Fieremans N , et al. (2016)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.[insA;delCTGGT] - frameshift_variant;frameshift_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.840C>G p.Tyr280Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3545del p.Glu1182GlyfsTer14 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.583G>C p.Ala195Pro missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.509G>A p.Arg170Gln missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.1676+2T>C p.? splice_site_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.3583-6G>A p.Val1195AlafsTer27 splice_site_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.3788_3794delTTGGCAG p.Ile1263Serfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.1676+5G>A p.? splice_site_variant De novo - - 28576131 Prchalova D , et al. (2017)
c.490C>T p.Arg164Ter stop_gained De novo - - 28708303 Chrot E , et al. (2017)
c.3190C>T p.Gln1064Ter stop_gained De novo - - 28708303 Chrot E , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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.

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

07-01-2017
1S

Initial score established: 1S

Description

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.

CNVs associated with SYNGAP1(1 CNVs)
6p21.32 21 Deletion-Duplication 30  /  261
Animal Models associated with SYNGAP1(9 Models)
SYNGAP1_1_KO_HM Genetic
SYNGAP1_1_KO_HT Genetic
SYNGAP1_3_CKO_HM Genetic
SYNGAP1_4_KO_HM Genetic
SYNGAP1_4_KO_HT Genetic
SYNGAP1_6_CKO_HT Genetic
SYNGAP1_7_CKI_HT Genetic
SYNGAP1_8_KO_HT Genetic
SYNGAP1_9_KO_FMR1_DM Genetic
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