ClinVar Miner

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

dbSNP: rs45446697
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics, part of Exact Sciences RCV003389629 SCV000305146 uncertain significance TSC2-related condition 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.
Invitae RCV000535683 SCV000644236 pathogenic Tuberous sclerosis 2 2023-12-29 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; Invitae). ClinVar contains an entry for this variant (Variation ID: 50185). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001797054 SCV002038804 uncertain significance not provided 2023-08-10 criteria provided, single submitter clinical testing Reported as a benign variant in published literature; however, additional information was not provided (Au et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-10C>A; This variant is associated with the following publications: (PMID: 26540169, 10735580, 17304050)
Genome-Nilou Lab RCV000535683 SCV002041327 benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
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 uncertain significance Isolated focal cortical dysplasia type II 2023-09-07 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000043454 SCV000067263 not provided Tuberous sclerosis syndrome no assertion provided curation

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