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Genetic epilepsy syndromes

Gene: VAMP2

Green List (high evidence)

VAMP2 (vesicle associated membrane protein 2)
EnsemblGeneIds (GRCh38): ENSG00000220205
EnsemblGeneIds (GRCh37): ENSG00000220205
OMIM: 185881, Gene2Phenotype
VAMP2 is in 7 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:46 a.m. | Last Modified: 9 Sep 2019, 10:46 a.m.
Panel Version: 1.321
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

Not associated with disease on OMIM. Salpietro et al, 2019 (30929742) - neurodevelopmental disorder characterised by axial hypotonia, ID and autistic features. 5 unrelated individuals, 3/5 had seizures (different types), all 5 had abnormal EEGs. 3 missense reported S75P, F77S and E78A and two inframe dels Val43del and Ile45del. All variants in the v-SNARE domain - highly conserved domain. Replacement analysis shows S75P and and E78A disrupt Hydrogen bonds.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Catherine Snow (Genomics England)

Green List (high evidence)

VAMP2 was identified due to a expert review by Konstantinos Varvagiannis on Salpietro et al. (PMID: 30929742). Literature reports 5 individuals, all with heterozygous de novo variants in VAMP2 and moderate/severe ID and ASD. All individuals had undergone trip sequencing. Epilepsy is reported in 3 of the individuals and all 5 have abnormal EEGs.
VAMP2 was identified among other potential genes associated with epilepsy by Baghel et al. (PMID:27458546), although they suggested a synergistic relationship with STX1A.
Functional work using a mouse model (PMID: 22183055)
VAMP2 is currently not associated with epilepsy in OMIM or G2P. There is sufficient number of affected individuals with functional support to make VAMP2 Green.
Created: 27 Jun 2019, 1:21 p.m. | Last Modified: 15 Jul 2019, 1:29 p.m.
Panel Version: 0.72

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Gene added in the ID panel (comments below). Epilepsy is a feature of this disorder (observed in 3 unrelated individuals, each with different VAMP2 variant).
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Salpietro et al. (2019 - PMID: 30929742 - DDD study among the co-authors) report on 5 individuals each with private heterozygous de novo variants in VAMP2.

The overlapping phenotype consisted among others of hypotonia with DD, moderate/severe ID and ASD (all in 5/5). Other features included the presence of clinical seizures (3/5 - EEG anomalies observed in all individuals), variable Rett-like stereotypies, hyperkinetic movements, central visual impairment. OFC was normal in all subjects.

VAMP2 encodes the vesicular SNARE protein synaptobrevin-2 which - along with its partners (syntaxin-1A and synaptosomal-associated protein 25) - mediates fusion of synaptic vesicles for the release of neurotransmitters. A number of synaptic proteins involved in Ca+2-regulated neurotransmitter release (eg. Munc18 encoded by STXBP1) regulate the fusion of synaptic vesicles, although SNAREs alone are sufficient for this process.

All variants localized in the v-SNARE domain (aa 31-91 - of 116 total residues - NP_0055047.2) with some phenotypic differences between variants localizing in the C-terminal end of the v-SNARE domain compared to those localizing in its proximal part. The following 3 missense variants and 2 in-frame deletions were reported (using NM_014232 as reference): c.223T>C or p.Ser75Pro - c.233A>C or p.Glu78Ala - c.230T>C or p.Phe77Ser - c.128_130delTGG or p.Val43del and c.135_137delCAT or p.Ile45del.

Functional studies were performed for 2 missense variants and were suggestive of impairment in vesicle fusion for the Ser75Pro variant. The fusion profile for Glu78Ala was however similar to wt. Upon Munc18-activated conditions, wt vesicle fusion was 2-fold increased, in contrast to a >90% loss-of-function effect which was observed for the Ser75Pro variant. Munc18 was however able to activate vesicle fusion mediated by the Glu78Ala variant. When using mixed v-liposomes (50:50 Wildtype:Ser75Pro mutant) the fusion profile was identical to the profile of homogeneous samples containing only the mutant protein which was suggestive of dominant interference of the mutant with wildtype.

In gnomAD, VAMP2 has a (low) Z-score and pLI of 1.41 and 0.89 respectively.

The authors comment that mutations in other genes encoding presynaptic proteins involved in Ca+2-regulated neurotransmitter release (eg SNAP25, STXBP1, etc) have been identified in other neurological disorders (with ID as a feature).

VAMP2 is not associated with any phenotype in OMIM or G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories.

As a result, VAMP2 can be considered for inclusion in the ID panel probably as green (5 individuals, degree of ID relevant) or amber.
Sources: Literature
Created: 7 Apr 2019, 4:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Autistic behavior; Stereotypic behavior; Seizures; Abnormality of movement; Cortical visual impairment

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Cortical visual impairment
  • Seizures
  • Stereotypic behavior
  • Generalized hypotonia
  • Intellectual disability
  • Abnormality of movement
  • Global developmental delay
  • Generalized hypotonia, Global developmental delay, Intellectual disability, Autistic behavior, Stereotypic behavior, Seizures, Abnormality of movement, Cortical visual impairment
  • Autistic behavior
OMIM
185881
Clinvar variants
Variants in VAMP2
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to VAMP2.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to VAMP2.

22 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to VAMP2. Source Expert Review was added to VAMP2. Added phenotypes Generalized hypotonia, Global developmental delay, Intellectual disability, Autistic behavior, Stereotypic behavior, Seizures, Abnormality of movement, Cortical visual impairment for gene: VAMP2 Publications for gene VAMP2 were changed from 30929742 to 27458546; 22183055; 30929742 Rating Changed from No List (delete) to Green List (high evidence)

7 Apr 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: VAMP2 was added gene: VAMP2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: VAMP2 were set to 30929742 Phenotypes for gene: VAMP2 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Autistic behavior; Stereotypic behavior; Seizures; Abnormality of movement; Cortical visual impairment Penetrance for gene: VAMP2 were set to unknown Review for gene: VAMP2 was set to GREEN