Developmental Brain Disorder Gene Database

LoF Variant Gene

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Tier

1

SYNGAP1

HGNC:11497 (protein-coding gene)

synaptic Ras GTPase activating protein 1

Unique Cases:
113
Disorders:
ID, ASD, EP, ADHD, SCZ, CP
Last Updated:
September 1, 2022

Summary
Cases
Publications
External

Gene Summary:

DBD Genes Classification
SYNGAP1 is a High Confidence candidate gene classified as Tier 1. Tier 1 genes have three or more de novo pathogenic loss-of-function variants.
Gene Function
Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR-mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term lea... (Source: Uniprot)
Previous symbols
No previous symbols
Alias symbols
SYNGAP, RASA5, KIAA1938
Chromosomal Location
6p21.32
Genomic Coordinates
GRCh37:chr6:33387847-33421466
GRCh38:chr6:33420065-33453689
Associated Disorders
Intellectual Disability, Autism, Epilepsy, Attention Deficit Hyperactivity Disorder, Cerebral Palsy

Predictive Scores:

HI Score (Decipher)

19.65

pLI (gnomAD)

1.00

LOEUF (gnomAD)

0.05

Classifications from External Sources:

SFARI Score (SFARI)

1

DDG2P Classification (DDG2P)

Definitive

ClinGen Classification (ClinGen)

Definitive1

GenCC Classification (GenCC)

Definitive2 Supportive3

Publications:

Benson KA et. al., A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability., Eur J Hum Genet, 2020
Tan CA et. al., Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis., Clin Genet, 2016
Dyment DA et. al., Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study., Clin Genet, 2015
Helbig KL et. al., Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy., Genet Med, 2016
Costain G et. al., Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy., Neuroscience, 2019
Lee H et. al., Clinical exome sequencing for genetic identification of rare Mendelian disorders., JAMA, 2014
Iossifov I et. al., The contribution of de novo coding mutations to autism spectrum disorder., Nature, 2014
Deciphering Developmental Disorders Study. et. al., Large-scale discovery of novel genetic causes of developmental disorders., Nature, 2015
De Rubeis S et. al., Synaptic, transcriptional and chromatin genes disrupted in autism., Nature, 2014
Redin C et. al., Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing., J Med Genet, 2014
Jang SS et. al., Diagnostic Yield of Epilepsy Panel Testing in Patients With Seizure Onset Within the First Year of Life., Front Neurol, 2019
Kothur K et. al., Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy., Seizure, 2018
Kim SY et. al., Dissecting the phenotypic and genetic spectrum of early childhood-onset generalized epilepsies., Seizure, 2019
Halvardson J et. al., Mutations in HECW2 are associated with intellectual disability and epilepsy., J Med Genet, 2016
Guo H et. al., Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model., Mol Autism, 2018
Aspromonte MC et. al., Characterization of intellectual disability and autism comorbidity through gene panel sequencing., Hum Mutat, 2019
Hamdan FF et. al., Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation., N Engl J Med, 2009
Berryer MH et. al., Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency., Hum Mutat, 2013
Hamdan FF et. al., De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism., Biol Psychiatry, 2011
Fernández-Marmiesse A et. al., Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients., Front Neurosci, 2019
Chérot E et. al., Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients., Clin Genet, 2018
Vlaskamp DRM et. al., SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy., Neurology, 2019
Hamdan FF et. al., Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability., Am J Hum Genet, 2011
Ko A et. al., Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy., Epilepsy Res, 2018
Wang T et. al., De novo genic mutations among a Chinese autism spectrum disorder cohort., Nat Commun, 2016
Feliciano P et. al., Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes., NPJ Genom Med, 2019
Carvill GL et. al., Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1., Nat Genet, 2013
Vissers LE et. al., A de novo paradigm for mental retardation., Nat Genet, 2010
Xu B et. al., De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia., Nat Genet, 2012
Takata A et. al., Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy., Nat Commun, 2019
Purcell SM et. al., A polygenic burden of rare disruptive mutations in schizophrenia., Nature, 2014
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NCBI: Gene

Integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes, and links to genome-, phenotype-, and locus-specific resources worldwide.
NCBI: Gene

Gene Reviews

An international point-of-care resource for busy clinicians, provides clinically relevant and medically actionable information for inherited conditions in a standardized journal-style format, covering diagnosis, management, and genetic counseling for patients and their families.
Gene Reviews

DECIPHER

DECIPHER (DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources) is an interactive web-based database which incorporates a suite of tools designed to aid the interpretation of genomic variants. DECIPHER enhances clinical diagnosis by retrieving information from a variety of bioinformatics resources relevant to the variant found in the patient.
DECIPHER

SFARI

SFARI Gene is an evolving online database designed to permit quick entrée into the genetics of autism, and to help researchers track the ever-expanding genetic risk factors that emerge in the literature.
SFARI

ClinGen

ClinGen is a National Institutes of Health (NIH)-funded resource dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research.
ClinGen

GenCC

The GenCC DB provides information pertaining to the validity of gene-disease relationships, with a current focus on Mendelian diseases.
GenCC

gnomAD

The Genome Aggregation Database (gnomAD) is a resource developed by an international coalition of investigators, with the goal of aggregating and harmonizing both exome and genome sequencing data from a wide variety of large-scale sequencing projects, and making summary data available for the wider scientific community.
gnomAD
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