ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2355+2_2355+5del

dbSNP: rs137854250
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000013215 SCV000255882 pathogenic Tuberous sclerosis 2 2014-12-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000013215 SCV003443062 pathogenic Tuberous sclerosis 2 2024-11-19 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 21 of the TSC2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Tuberous sclerosis (PMID: 10205261, 10533067, 19259131). In at least one individual the variant was observed to be de novo. This variant is also known as 2355+2delTAGG, c.2355+1_2355+4del, IVS20 + 1-4 delGTAG, 2373+2del4bp. ClinVar contains an entry for this variant (Variation ID: 12406). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19259131). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV000013215 SCV004101301 pathogenic Tuberous sclerosis 2 2023-07-27 criteria provided, single submitter clinical testing The TSC2 c.2355+2_2355+5del variant results in a deletion at the consensus splice donor site, which may result in splicing defects. This variant has been identified in at least five unrelated individuals with a phenotype consistent with tuberous sclerosis complex, including in one in which it occurred de novo (PMID: 10205261; 10533067; 19259131; 28968464; 34403804). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. PCR analysis of cDNA from a patient with the c.2355+2_2355+5del variant demonstrated aberrant splicing that resulted in a premature stop codon (PMID: 19259131). Based on the available evidence, the c.2355+2_2355+5del variant is classified as pathogenic for tuberous sclerosis.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV005229783 SCV005876121 pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing The TSC2 c.2355+2_2355+5del variant (rs137854250) is reported in the literature in individuals affected with tuberous sclerosis complex (Babol-Pokora 2021, Le Caignec 2009, Niida 1999, Rosset 2017). This variant is reported in ClinVar (Variation ID: 12406). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 21, and in vitro functional analyses demonstrate novel cryptic donor splice site and the generation of a premature stop codon (Le Caignec 2009). Based on available information, this variant is considered to be pathogenic. References: Babol-Pokora K et al. A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex. Eur J Med Genet. 2021 Oct;64(10):104309. PMID: 34403804. Le Caignec C. Three independent mutations in the TSC2 gene in a family with tuberous sclerosis. Eur J Hum Genet. 2009 Sep;17(9):1165-70. PMID: 19259131. Niida Y et al. Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum Mutat. 1999;14(5):412-22. PMID: 10533067. Rosset C et al. Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS One. 2017 Oct 2;12(10):e0185713. PMID: 28968464.
OMIM RCV000013215 SCV000033462 pathogenic Tuberous sclerosis 2 2009-09-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000042461 SCV000066252 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC2) RCV000042461 SCV000066773 not provided Tuberous sclerosis syndrome no assertion provided curation

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