ClinVar Miner

Submissions for variant NM_000548.3(TSC2):c.5260-1G>C (rs1057518103)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413128 SCV000491506 likely pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing The c.5260-1G>C variant in the TSC2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 41. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.5260-1G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on the currently available evidence, c.5260-1G>C is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000540578 SCV000644623 uncertain significance Tuberous sclerosis 2 2018-03-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron of the TSC2 gene. While It is not anticipated to result in an absent or disrupted protein product, it is expected to alter RNA splicing. This variant has not been reported in the literature in individuals with a TSC2-related disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547). However, this intronic change is in the acceptor splice site of the last intron and may not impact TSC2 protein function. Without additional functional and/or genetic data, this variant has been classified as Variant of Uncertain Significance.

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