ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.225+2T>C

dbSNP: rs397515105
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001035357 SCV001198682 uncertain significance Tuberous sclerosis 2 2023-12-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the TSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 834629). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV002221601 SCV002498954 uncertain significance not provided 2022-04-07 criteria provided, single submitter clinical testing Identified as a secondary finding in an individual undergoing whole exome sequencing (Kuo et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS2+2T>C; Targeted RNA studies in blood samples from the proband, father, and mother suggest altered RNA splicing. Wild type transcript was detected in all family members, with multiple aberrant splice products detected at lower levels. However, aberrant splice products, including exon 3 skipping resulting in an 87-bp deletion, predicted in-frame 29 amino acid loss at protein level, and premature stop codon, were unique in the proband's or father's blood samples and absent in the mother's blood sample.; This variant is associated with the following publications: (PMID: 32794656, 18466115)
Clinical Genomics Program, Stanford Medicine RCV001035357 SCV001427097 likely pathogenic Tuberous sclerosis 2 2019-11-14 no assertion criteria provided clinical testing The c.225+2T>C variant in the TSC2 gene has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant alters the canonical donor splice site in intron 3, which is predicted to result in abnormal gene splicing. Notably, a different nucleotide change at this position (c.225+2T>A) has been previously reported de novo in an individual with features of tuberous sclerosis complex (Nellist et al., 2015), suggesting the c.225+2T>C variant may similarly be associated with tuberous sclerosis complex. Heterozygous loss of function is an established mechanism of disease for the TSC2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.225+2T>C variant as likely pathogenic for tuberous sclerosis complex in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2]

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