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Genetic epilepsy syndromes

Gene: SCAMP5

Amber List (moderate evidence)

SCAMP5 (secretory carrier membrane protein 5)
EnsemblGeneIds (GRCh38): ENSG00000198794
EnsemblGeneIds (GRCh37): ENSG00000198794
OMIM: 613766, Gene2Phenotype
SCAMP5 is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Created: 24 Mar 2020, 1:39 p.m. | Last Modified: 24 Mar 2020, 1:39 p.m.
Panel Version: 2.20
PMID 32020363 reports a homozygous variant (NM_001178111:c.271C>T, p.R91W rs747966691) in two sibs of a Chinese consanguienious family, with early onset epilepsy and Parkinson’s disease (the heterozygous parents had a normal phenotype). The p.R91W knock-in mouse showed typical early-onset epilepsy and functional studies showed dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain. The patients with this variant did not show signs of autism, intellectual disability, or other growth and developmental disorders.
Created: 24 Mar 2020, 1:21 p.m. | Last Modified: 24 Mar 2020, 1:21 p.m.
Panel Version: 2.18
Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Created: 24 Mar 2020, 12:57 p.m. | Last Modified: 30 Mar 2020, 11:57 a.m.
Panel Version: 2.25
Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).
Created: 24 Mar 2020, 12:51 p.m. | Last Modified: 24 Mar 2020, 12:51 p.m.
Panel Version: 2.16

Ellen McDonagh (Genomics England Curator)

Comment on mode of pathogenicity: A dominant negative effect is predicted.
Created: 27 Nov 2019, 5:02 p.m. | Last Modified: 27 Nov 2019, 5:02 p.m.
Panel Version: 1.477
Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Created: 27 Nov 2019, 5:01 p.m. | Last Modified: 27 Nov 2019, 5:01 p.m.
Panel Version: 1.476

Konstantinos Varvagiannis (Other)

I don't know

PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures, behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Created: 11 Nov 2019, 5:20 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Abnormality of nervous system morphology
  • Behavioral abnormality
Tags
watchlist
OMIM
613766
Clinvar variants
Variants in SCAMP5
Penetrance
unknown
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

30 Mar 2020, Gel status: 2

Added Tag

Sarah Leigh (Genomics England Curator)

Tag watchlist tag was added to gene: SCAMP5.

24 Mar 2020, Gel status: 2

Set mode of pathogenicity

Sarah Leigh (Genomics England Curator)

Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other

24 Mar 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: scamp5 has been classified as Amber List (Moderate Evidence).

24 Mar 2020, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: scamp5 has been classified as Green List (High Evidence).

24 Mar 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: scamp5 has been classified as Amber List (Moderate Evidence).

24 Mar 2020, Gel status: 2

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for gene: SCAMP5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

24 Mar 2020, Gel status: 2

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

24 Mar 2020, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: SCAMP5 were set to 31439720; 20071347

27 Nov 2019, Gel status: 2

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other

27 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

Gene: scamp5 has been classified as Amber List (Moderate Evidence).

11 Nov 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: SCAMP5 was added gene: SCAMP5 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SCAMP5 were set to 31439720; 20071347 Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality Penetrance for gene: SCAMP5 were set to unknown Mode of pathogenicity for gene: SCAMP5 was set to Other Review for gene: SCAMP5 was set to AMBER