SYNGAP1

Gene Facts

• HGNC Symbol: SYNGAP1 (HGNC:11497)
• HGNC Name: synaptic Ras GTPase activating protein 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: SYNGAP, RASA5, KIAA1938
• %HI: 19.65
• pLI: 1
• LOEUF: 0.13
• Cytoband: 6p21.32
• Genomic Coordinates:

  GRCh37/hg19:	chr6:33387842-33421466
  GRCh38/hg38:	chr6:33418167-33453689

• MANE Select Transcript: NM_006772.3 ENST00000646630.1
• 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)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-27807
• ClinGen Curation ID: CCID:007962
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/09/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 26989088
  Mignot C et al., (2016) performed exome, or gene panel (SYNGAP1 and 18 other synaptic genes) sequencing on a cohort of 251 patients with neurodevelopmental disorders (NDD). Three de novo pathogenic heterozygous loss of function variants and one heterozygous 16.6kb deletion of exons 2-9 in SYNGAP1 gene were identified. This study described genotype and phenotype relationship of these 4 patients and additional 13 patients with variants in SYNGAP1 gene. Twelve of these variants from 17 unrelated affected individual had de novo loss of function (LoF) variant, and 4 loss of function variants of unknown inheritance (parents not tested). This study further reviewed a total 47 patients (including two monozygotic twins) carrying 43 different point mutation or indels limited to the SYNGAP1 gene. Pathogenic mutations in SYNGAP1 are distributed throughout the gene, especially in exons 5, 8 and 15, the three largest exons. The two first, two last exons, also exons 9 and 16, present in all known isoforms, seem to be spared. The epilepsy of patients with variants in exons 4–5 was mainly pharmacosensitive, whereas that of patients with mutations in exons 8–15 was mainly pharmacoresistant.
• PUBMED: 30541864
  Vlaskamp DRM et al., (2019) reported a cohort of 57 patients from Australia, Italy, the Netherlands, and China, who had epilepsy and mutations or microdeletions in SYNGAP1 gene. The mutations included 34 truncating (nonsense and frameshift mutations), 8 splice-site, and 11 missense/in-frame mutations and 4 microdeletions (4-13 genes including SYNGAP1 in all). 53 of the 57 are de novo, but no detailed methods were recorded. In general, truncating and splice-site mutations occur throughout SYNGAP1, while missense mutations mainly cluster in the protein domains. A milder outcome of SYNGAP1-DEE was observed significantly more frequently in patients with mutations in exons 1 to 4 compared with those with mutations in exons 5 to 19. They found concordant phenotypes in monozygotic twins, similar phenotypes in 2 siblings, variable phenotypes in individuals sharing the same mutation. This study concludes that SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
• PUBMED: 21237447 19196676
  Hamdan F et al., (2011) reported three de novo loss of function variants in SYNGAP1 gene by Sanger sequencing and 6 informative microsatellite markers. All three variants are absent in a total of 380 control subjects. These mutations are located in the vicinity of three other de novo truncating mutations previously reported by this group ( PMID: 19196676.). Hamdan F et al., (2009) reported three different de novo truncating mutations (K138X, R579X, and L813RfsX22) in 3 of 94 patients with nonsyndromic intellectual disability (ID) in SYNGAP1. ​They concluded that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic intellectual disability.
• PUBMED: 25533962
  Fitzgerald TW et al., (2015) reported 7 loss of function variants in SYNGAP1 genes from a series of 1133 patients through all 24 regional genetics services of the UK National Health Service and Republic of Ireland. Among the most commonly observed phenotypes were intellectual disability or developmental delay with ID by exome sequencing.
• PUBMED: 23708187
  Carvill GL et al., (2013) reported 5 truncating variants in SYNGAP1 in 5 of 500 patients with epilepsy. These SYNGAP1 variants account for 1% of case of epileptic encephalopathies (EE) in this cohort using a targeted massively parallel resequencing of 65 genes.
• PUBMED: 26079862
  Parker MJ et al., (2015) described seven de novo loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion) in individuals with moderate-to-severe ID, epilepsy by trio‐based exome sequencing. Each affected individual has also had a high‐resolution analysis for copy number abnormalities using array‐based comparative genomic hybridization (aCGH). Putative de novo mutations were identified from exome data. The individual with microdeletion of 0.39 at 6p21.32p21.31 encompassing the entire SYNGAP1 gene and 18 other genes. The clinical features of the individuals reported showed significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity