Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000233818 | SCV000285453 | pathogenic | Tuberous sclerosis 2 | 2019-01-10 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Functional studies using animal models have shown that the C-terminus of the TSC2 protein is involved in tumor suppression (PMID: 8799170, 17379185). Multiple frameshift variants, including c.5340_5371del (p.1784Alafs*?) and c.5405_5408dup (p.Phe1803Leufs*42) located downstream of this variant, have been reported as de novo disease-causing variants in individuals affected with tuberous sclerosis complex (PMID: 10205261, 9328481, 24789117). This suggests that frameshift variants affecting the very C-terminus of TSC2 impact protein function and cause disease. This variant has not been reported in the literature in individuals with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 238080). This sequence change deletes 1 nucleotide from exon 42 of the TSC2 mRNA (c.5266delG), causing a frameshift at codon 1756. This creates a premature translational stop signal in the last exon of the TSC2 mRNA (p.Glu1756Argfs*70). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the TSC2 protein. |
| ARUP Laboratories, |
RCV003114395 | SCV003800331 | likely pathogenic | not provided | 2022-03-04 | criteria provided, single submitter | clinical testing | The TSC2 c.5266delG; p.Glu1756ArgfsTer70 variant (rs878854118), to our knowledge, is not reported in the medical literaturE. However, frameshift variants that occur downstream of this variant have been described in affected individuals and are considered pathogenic (Ding 2020, Lindy 2018, Liu 2018). The variant is listed in the ClinVar database (Variation ID: 238080) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the TSC2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated TSC2 protein. This region of TSC2 encodes the GAP domain, critical for tumor suppression (Jin 1996, Momose 2007). Based on available information, this variant is classified as likely pathogenic. References: Ding Y et al. Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. Front Genet. 2020 Mar 10;11:204. PMID: 32211034. Jin F et al. Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C-terminal region. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9154-9. PMID: 8799170. Lindy AS et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018 May;59(5):1062-1071. PMID: 29655203. Liu J et al. Novel and de novo mutations in pediatric refractory epilepsy. Mol Brain. 2018 Sep 5;11(1):48. PMID: 30185235 Jin F et al. Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C- Momose S et al. N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo. Biochem Biophys Res Commun. 2007 May 11;356(3):693-8. PMID: 17379185. |