ClinVar Miner

Submissions for variant NM_138967.4(SCAMP5):c.538G>T (p.Gly180Trp)

dbSNP: rs1184981709
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001092613 SCV001249195 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001265752 SCV001443921 pathogenic Inborn genetic diseases 2021-10-04 criteria provided, single submitter clinical testing The c.538G>T (p.G180W) alteration is located in exon 8 (coding exon 6) of the SCAMP5 gene. This alteration results from a G to T substitution at nucleotide position 538, causing the glycine (G) at amino acid position 180 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple unrelated patients with seizures, developmental delay, intellectual disability, and abnormal neurological exam findings. Some patients were also reported to have autism spectrum disorder and/or dysmorphic facial features (Hubert, 2020; Jiao 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.G180W alteration decreased protein levels compared to wild type protein when expressed in the Drosophila fat body using the corresponding alteration, p.G302W, in the fly homolog. Additionally, expression of the p.G302W alteration in Drosophila showed abnormal eye formation and disturbed the normal fly neurological phenotype (Hubert, 2020). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
3billion, Medical Genetics RCV001779115 SCV002014729 likely pathogenic Global developmental delay 2021-10-25 criteria provided, single submitter clinical testing The variant has been previously reported as de novo insimilarly affected unrelated individual (PMID:31439720, PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.649, 3Cnet: 0.848, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV001092613 SCV002562356 pathogenic not provided 2022-08-09 criteria provided, single submitter clinical testing Published functional studies using Drosophila fly models showed reduced protein levels and suggested a dominant-negative effect (Hubert et al., 2020); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33663553, 33390987, 31439720)
Illumina Laboratory Services, Illumina RCV003389252 SCV004101306 likely pathogenic SCAMP5-related neurodevelopmental disorder with autistic features and seizures 2023-06-01 criteria provided, single submitter clinical testing The SCAMP5 c.538G>T (p.Gly180Trp) missense variant has been reported in a de novo state in six unrelated individuals with developmental delay, seizures, motor disorders, behavioral differences, and abnormalities on brain MRI (PMID: 31439720; 33390987). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies of this variant conducted in a Drosophila knock-in model suggest it has a dominant-negative effect (PMID: 31439720). This variant has been classified as pathogenic or likely pathogenic by four submitters in ClinVar. Based on the available evidence, the c.538G>T (p.Gly180Trp) variant is classified as likely pathogenic for SCAMP5-related neurodevelopmental disorder with autistic features and seizures.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV003444151 SCV004171244 likely pathogenic Macrocephaly-developmental delay syndrome 2023-11-30 criteria provided, single submitter clinical testing
OMIM RCV001092613 SCV001441621 uncertain significance not provided 2020-11-10 no assertion criteria provided literature only

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