Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000693280 | SCV000821142 | uncertain significance | Tuberous sclerosis 2 | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change affects codon 1663 of the TSC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TSC2 protein. This variant also falls at the last nucleotide of exon 38, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 571995). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Ambry Genetics | RCV002343473 | SCV002645645 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-17 | criteria provided, single submitter | clinical testing | The c.4989G>A variant (also known as p.K1663K), located in coding exon 37 of the TSC2 gene, results from a G to A substitution at nucleotide position 4989. This nucleotide substitution does not change the lysine at codon 1663. However, this change occurs in the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003465587 | SCV004205107 | uncertain significance | Isolated focal cortical dysplasia type II | 2023-03-24 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003892547 | SCV004713316 | uncertain significance | TSC2-related condition | 2024-01-11 | criteria provided, single submitter | clinical testing | The TSC2 c.4989G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide of an exon and is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant was reported as a variant of uncertain significance in a large patient cohort undergoing hereditary cancer testing (Kamps-Hughes et al. 2023. PubMed ID: 36563937). Large scale RNA sequencing in patient leukocytes suggested that this variant might alter splicing,; however, the detailed splicing change was not available (Table S4, Kamps-Hughes et al. 2023. PubMed ID: 36563937). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/571995/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |