Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000467054 | SCV000544522 | uncertain significance | Tuberous sclerosis 2 | 2023-07-26 | criteria provided, single submitter | clinical testing | This variant results in the deletion of an acceptor splice site in intron 41 and the first 20 nucleotides of exon 42 (c.5260-9_5279del) of the TSC2 gene. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of the last exon (exon 42) and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 406091). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. |
| Gene |
RCV001558132 | SCV001780017 | uncertain significance | not provided | 2018-11-12 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server) |
| Ambry Genetics | RCV003380570 | SCV004091346 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-14 | criteria provided, single submitter | clinical testing | The c.5260-9_5279del29 variant results from a deletion of 29 nucleotides between positions 5260-9 and 5279 and involves the canonical splice acceptor site before coding exon 41 of the TSC2 gene. The canonical splice acceptor site is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. However, this alteration occurs at the 3' terminus of the TSC2 gene and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of this alteration is unknown; Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |