ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.976-15G>A (rs45517150)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189971 SCV000243642 pathogenic not provided 2017-07-27 criteria provided, single submitter clinical testing The c.976-15 G>A splice site pathogenic variant in the TSC2 gene has been previously reported in multiple unrelated individuals with a clinical diagnosis of tuberous sclerosis (Mayer et al., 1999; Dabora et al., 2001; Au et al, 2007; TSC2 LOVD). This pathogenic variant damages the natural splice acceptor site in intron 10 (referred to as intron 9 in previous publications due to the use of alternative nomenclature). In vitro mRNA analysis indicates the c.976-15 G>A pathogenic variant leads to skipping of exon 10 and the use of a cryptic splice acceptor site in exon 11, resulting in abnormal gene splicing (Mayer et al., 1999; Mayer et al., 2000).
Invitae RCV000465503 SCV000544321 pathogenic Tuberous sclerosis 2 2019-09-30 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the TSC2 mRNA. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (rs45517150, ExAC no frequency). This variant has been reported in the literature in multiple individuals meeting clinical diagnostic criteria for tuberous sclerosis complex (TSC), where it was identified as a de novo or mosaic variant in some individuals (PMID: 10533066, 11112665, 21520333, 26540169). It is also known as IVS9-15G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 49396). Experimental studies using patient-derived RNA have shown that this variant affects mRNA splicing leading to two aberrant transcripts: one transcript missing in-frame exon 11 (referred to as exon 10), and the other missing the first 56 nucleotides in exon 11 which creates a frameshift and premature stop codon (p.Met327HisfsX5) (PMID: 11068191, 10533066). RNA secondary structure analysis indicated that this variant disrupts the structural motif between the splicing branchpoint and the splice acceptor site (PMID: 11068191). For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042656 SCV000066451 not provided Tuberous sclerosis syndrome no assertion provided curation

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.