SYNGAP1

protein-coding

synaptic Ras GTPase activating protein 1, the group of MicroRNA protein coding host genes|C2 and RasGAP domain containing

Gene summary

This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

MANE transcript

NM_006772.3

Inheritance

ClinVar variants

P:470U:573B:622

Top phenotype

Intellectual developmental disorder, autosomal dominant 5

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr6:33,419,661-33,453,689

External References & Databases

Ensembl (ENSG00000197283)

Transcript & Mutation Effects

hg38 • Region Span ~34.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SYNGAP1-related developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0034099

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012960

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

SYNGAP1 was first reported in relation to AD nonsyndromic intellectual disability in 2009 (Hamdan et al, 2009). At least 129 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. While a large number of pathogenic (mostly de novo) variants have been identified in patients with a complex neurodevelopmental disorder, there appears to be little correlation between variant location and severity of ID, epilepsy, or autism symptoms. In summary, SYNGAP1 is definitively associated with AD complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Epilepsy GCEP on 4/2/2019.

intellectual developmental disorder, autosomal dominant 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012960

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012960

Submitter: PanelApp Australia

myoclonic-astatic epilepsySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016025

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 5AD

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: 19196676; 23020937

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SYNGAP1 variants in ClinVar

43 Conditions Cataloged

Intellectual disability, autosomal dominant 5Total: 1488

not providedTotal: 542

Inborn genetic diseasesTotal: 237

not specifiedTotal: 159

SYNGAP1-related disorderTotal: 103

Complex neurodevelopmental disorderTotal: 19

Intellectual disabilityTotal: 14

SeizureTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006772.3. 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	3 clinvar	7 clinvar	398 clinvar	6 clinvar	415
missense	14 clinvar	65 clinvar	558 clinvar	161 clinvar	53 clinvar	851
nonsense	70 clinvar	23 clinvar	3 clinvar			96
start loss				1 clinvar		1
frameshift	192 clinvar	44 clinvar	2 clinvar	3 clinvar		241
splice donor/acceptor (+/-2bp)	27 clinvar	31 clinvar	3 clinvar			61
Total	304	166	573	563	59	1665

Highest pathogenic variant AF is 0.000027364835

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006772.3	RefSeq	NP_006763.2	19	MANE Select
ENST00000646630.1	Ensembl	ENSP00000496007.1	19	MANE Select
NM_001130066.2	RefSeq	NP_001123538.1	18	Standard
ENST00000293748.9	Ensembl	ENSP00000293748.6	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
syngap1b	Danio rerio	Structure: whole organism Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

syngap1b

Danio rerio

Structure: whole organism

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ras signaling pathway - Homo sapiens (human)
Ras Signaling
Regulation of Ras family activation
Signal Transduction
Regulation of RAS by GAPs

Biological Process

MAPK cascade
Ras protein signal transduction
pattern specification process
visual learning
dendrite development

Molecular Function

GTPase activator activity
SH3 domain binding

Cellular Component

cytosol
plasma membrane
postsynaptic density
dendritic shaft
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418600
Coding exons: 19
Length: 33620
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125742
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.60	351	796	0.441	0.0000537	8688
Missense (PolyPhen)		128	347.34	0.36852		3803
Synonymous	1.65	287	325	0.883	0.0000203	2808
Loss of Function	6.97	0	56.5	0.00	0.00000350	625

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 learning and memory deficits (By similarity). {ECO:0000250}.;
Disease: DISEASE: Mental retardation, autosomal dominant 5 (MRD5) [MIM:612621]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD5 patients show global developmental delay with delayed motor development, hypotonia, moderate-to- severe mental retardation, and severe language impairment. Epilepsy and autism can be present in some patients. {ECO:0000269|PubMed:19196676, ECO:0000269|PubMed:21076407, ECO:0000269|PubMed:21237447, ECO:0000269|PubMed:23161826, ECO:0000269|PubMed:23708187}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

RVIS EVS: -1.15
RVIS percentile EVS: 6.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.755

Gene Damage Prediction

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