ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2838-122G>A

dbSNP: rs1567489890
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000691799 SCV000819591 pathogenic Tuberous sclerosis 2 2024-05-08 criteria provided, single submitter clinical testing This sequence change falls in intron 25 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 may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 25927202, 29932062, 32211034, 32581362). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 570837). Studies have shown that this variant results in the insertion of 120 nucleotides upstream of exon 26 and introduces a premature termination codon (PMID: 25927202). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001584566 SCV001818072 pathogenic not provided 2021-04-09 criteria provided, single submitter clinical testing Published functional studies suggest that c.2838-122 G>A results in a truncated protein due to abnormal splicing (Nellist et al., 2015).; In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 32581362, 32211034, 30904096, 21520333, 27406250, 29932062, 25927202)
Genome-Nilou Lab RCV000691799 SCV002040962 pathogenic Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002440452 SCV002750466 pathogenic Hereditary cancer-predisposing syndrome 2023-06-12 criteria provided, single submitter clinical testing The c.2838-122G>A intronic pathogenic mutation results from a G to A substitution 122 nucleotides upstream from coding exon 25 in the TSC2 gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TSC2-related disease, including having been identified as de novo in one patient (Ambry internal data; Nellist, M et al. BMC Med Genet 2015 Feb;16:10; Ding, Y et al. Front Genet 2020 Mar;11:204.). This nucleotide position is 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 acceptor site. RNA studies have demonstrated this alteration to create a novel acceptor and result in a transcript expected to undergo nonsense-mediated mRNA decay (Nellist, M et al. BMC Med Genet 2015 Feb;16:10). 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003985 SCV001162011 likely pathogenic Cortical tubers; Neoplasm no assertion criteria provided research

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