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

dbSNP: rs45517150

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189971	SCV000243642	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In vitro mRNA analysis indicates the c.976-15G>A variant leads aberrant splicing of exon 11 (Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10533066, 11112665, 26540169, 17304050, 19369101, 28968464, 33278787, 18466115, 11068191)
Invitae	RCV000465503	SCV000544321	pathogenic	Tuberous sclerosis 2	2023-05-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 11 (referred to as exon 10), but is expected to preserve the integrity of the reading-frame (PMID: 10533066, 11068191). ClinVar contains an entry for this variant (Variation ID: 49396). This variant is also known as IVS9-15G>A. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 10533066, 11112665, 21520333, 26540169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
3billion	RCV000465503	SCV002012234	pathogenic	Tuberous sclerosis 2	2021-10-02	criteria provided, single submitter	clinical testing	Intronic variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 11068191, 10533066).The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26540169, 11112665, PS4). 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: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000465503	SCV002040926	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000465503	SCV002559890	pathogenic	Tuberous sclerosis 2	2022-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483043	SCV002789771	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-10-26	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002483043	SCV003920601	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2022-09-23	criteria provided, single submitter	clinical testing	This variant has been reported in more than 10 individuals with a clinical diagnosis or suspicion of tuberous sclerosis, including as de novo in at least one individual and in the mosaic state in another (Selected publications: Mayer 1999 PMID: 10533066; Dabora 2001 PMID: 11112665; Tyburczy 2015 PMID: 26540169; Wang 2021 PMID: 33278787). This variant is absent from large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic (Variation ID: 49396). Transcriptional analyses demonstrated that this variant leads to two abnormal transcripts: one with the in-frame skipping of exon 11, and one with the activation of a cryptic splice acceptor in exon 11 that results in the deletion of 56 nucleotides, introducing a frameshift and premature stop codon (Mayer 1999 PMID: 10533066; Mayer 2000 PMID: 11068191). Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID: 28222202). In summary, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390733	SCV004118878	pathogenic	TSC2-related condition	2023-05-08	criteria provided, single submitter	clinical testing	The TSC2 c.976-15G>A variant is predicted to interfere with splicing. In the literature this variant is also referred to as IVS9-15G>A. Based on available splicing prediction programs (Alamut Visual Plus v1.6.1), this variant creates a cryptic splice acceptor site. Functional studies have also shown that this variant leads to skipping of exon 10 and the creation of a cryptic splice acceptor in exon 10 (Mayer et al. 1999. PubMed ID: 10533066; Mayer et al. 2000. PubMed ID: 11068191). This variant has been reported in individuals with tuberous sclerosis complex (TSC) (Mayer et al. 1999. PubMed ID: 10533066; Dabora et al. 2000. PubMed ID: 11112665; Mayer et al. 2000. PubMed ID: 11068191; Tyburczy et al. 2015. PubMed ID: 26540169; Rosset et al. 2017. PubMed ID: 28968464). This variant has also been reported in TSC patients in the presumed mosaic state (allelic frequency <50%) (Tyburczy et al. 2015. PubMed ID: 26540169). This variant has also been reported in an individual with status epilepticus (Wang et al. 2020. PubMed ID: 33278787). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/49396/). This variant is interpreted as pathogenic.
Tuberous sclerosis database (TSC2)	RCV000042656	SCV000066451	not provided	Tuberous sclerosis syndrome		no assertion provided	curation