Intellectual disability - microarray and sequencing
Gene: SCAMP5
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
PMIDs: 31439720; 33390987 report a total of six indiviuals with de novo heterozygous SCAMP5, p.Gly180Trp variants. All cases had neurodevelopmental disorders including intellectual disability and seizures.Created: 22 Sep 2022, 1:48 p.m. | Last Modified: 22 Sep 2022, 1:48 p.m.
Panel Version: 3.1726
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 22 Sep 2022, 1:38 p.m. | Last Modified: 22 Sep 2022, 1:38 p.m.
Panel Version: 3.1726
After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changedCreated: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
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: 3.19
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, 1:38 p.m. | Last Modified: 22 Sep 2022, 1:40 p.m.
Panel Version: 3.1726
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, 12:52 p.m. | Last Modified: 24 Mar 2020, 12:52 p.m.
Panel Version: 3.17
Two unrelated individuals with same de novo missense variant with good functional evidence (animal model).Created: 16 Feb 2020, 6:27 a.m. | Last Modified: 16 Feb 2020, 6:27 a.m.
Panel Version: 3.3
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability; seizures; autism
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
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: 2.1126
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: LiteratureCreated: 11 Nov 2019, 5:18 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
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag gene-checked tag was added to gene: SCAMP5.
Tag Q3_22_rating was removed from gene: SCAMP5.
Source Expert Review Green was added to SCAMP5. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag watchlist was removed from gene: SCAMP5. Tag Q3_22_rating tag was added to gene: SCAMP5.
Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363; 33390987
Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Source NHS GMS was added to SCAMP5.
Tag watchlist tag was added to gene: SCAMP5.
Mode of pathogenicity for gene: SCAMP5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SCAMP5 were set to 31439720; 20071347
Gene: scamp5 has been classified as Amber List (Moderate Evidence).
gene: SCAMP5 was added gene: SCAMP5 was added to Intellectual disability. 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 Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: SCAMP5 was set to AMBER