Submissions for variant NM_000548.5(TSC2):c.1362-10C>A

dbSNP: rs45446697

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV004528239	SCV000305146	uncertain significance	TSC2-related disorder	2023-05-10	criteria provided, single submitter	clinical testing	The TSC2 c.1362-10C>A variant is predicted to interfere with splicing. The c.1362-10 C>A intronic variant in the TSC2 gene has been reported in individuals affected with tuberous sclerosis, and has been reported to segregate with affected status within a family; however, minimal details were provided (Tyburczy et al. 2015. PubMed ID: 26540169; Choy et al. 1999. PubMed ID: 10735580; Au et al. 2007. PubMed ID: 17304050; https://databases.lovd.nl/shared/variants/TSC2). This variant is predicted to abolish the canonical splice acceptor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. In ClinVar this variant has conflicting classifications including pathogenic, likely pathogenic, uncertain significance, and benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/50185/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535683	SCV000644236	pathogenic	Tuberous sclerosis 2	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis complex (PMID: 26540169; internal data). ClinVar contains an entry for this variant (Variation ID: 50185). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001797054	SCV002038804	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Reported as a benign variant in published literature; however, additional information was not provided (PMID: 17304050); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS12-10C>A; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10735580, 26540169, 17304050)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000535683	SCV002515805	uncertain significance	Tuberous sclerosis 2	2021-11-30	criteria provided, single submitter	research	ACMG codes: PM2, PP3
Ambry Genetics	RCV002381328	SCV002699633	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-05	criteria provided, single submitter	clinical testing	The c.1362-10C>A intronic pathogenic mutation results from a C to A substitution 10 nucleotides upstream from coding exon 13 in the TSC2 gene. This alteration has been observed in many individuals with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Personal communication; Tyburczy ME et al. PLoS Genet, 2015 Nov;11:e1005637; Choy YS et al. Ann Hum Genet, 1999 Sep;63:383-91). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003466896	SCV004206851	likely pathogenic	Isolated focal cortical dysplasia type II	2024-06-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001797054	SCV005622613	likely pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Some individuals were reported to have a variable and/or mild presentation (PMID: 10735580, 17304050, 26540169, internal patient(s), and personal communication related to ClinVar ID: 50185, Accession: SCV000644236.7). This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may interfere with normal RNA splicing. RT-PCR analysis was unable to confirm an effect on RNA splicing, however it is uncertain whether the detection method used would identify a small, in-frame length change of this exon (PMID: 26540169).
Tuberous sclerosis database (TSC2)	RCV000043454	SCV000067263	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Genome-Nilou Lab	RCV000535683	SCV002041327	benign	Tuberous sclerosis 2	2021-11-07	flagged submission	clinical testing