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Early onset or syndromic epilepsy v3.35 SCAMP5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v3.30 SCAMP5 Arina Puzriakova Tag watchlist was removed from gene: SCAMP5.
Tag Q2_21_rating was removed from gene: SCAMP5.
Early onset or syndromic epilepsy v3.29 SCAMP5 Arina Puzriakova reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.28 SCAMP5 Arina Puzriakova Source Expert Review Green was added to SCAMP5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.491 SCAMP5 Sarah Leigh commented on gene: SCAMP5: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.490 SCAMP5 Sarah Leigh Source NHS GMS was added to SCAMP5.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (18/02/2021). At single heterozygous variant (NM_001178111.1: c.538G>T, p.Gly180Trp) has been reported to be associated with intellectual disability; seizures; autism in at least six unrelated cases (PMID 33390987; 31439720).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Added comment: Comment on phenotypes: OMIM does not have a phenotype associated with variants in this gene (18/02/21).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Phenotypes for gene: SCAMP5 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Early onset or syndromic epilepsy v2.301 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439720, 33390987; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh Tag watchlist tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh changed review comment from: 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. ; to: 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.
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Added comment: 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.
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh changed review comment from: 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.; to: 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.
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh commented on gene: SCAMP5: 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.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Added comment: 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.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Added comment: 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.
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Added comment: 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).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.15 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.14 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Added comment: Comment on mode of pathogenicity: A dominant negative effect is predicted.
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Added comment: Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.405 SCAMP5 Konstantinos Varvagiannis 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
Added comment: 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