ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5266del (p.Glu1756fs) (rs878854118)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233818 SCV000285453 pathogenic Tuberous sclerosis 2 2016-12-21 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 42 of the TSC2 mRNA (c.5266delG), causing a frameshift at codon 1756. This creates a premature translational stop signal in the last exon of the TSC2 mRNA (p.Glu1756Argfs*70). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the TSC2 protein. This variant has not been reported in the literature in individuals with a TSC2-related disease. Multiple frameshift variants, including c.5340_5371del (p.1784Alafs*?) and c.5405_5408dup (p.Phe1803Leufs*42) located downstream of this variant, have been reported as de novo disease-causing variants in individuals affected with tuberous sclerosis complex (PMID: 10205261, 9328481, 24789117). This suggests that frameshift variants affecting the very C-terminus of TSC2 impact protein function and cause disease. Functional studies using animal models have shown that the C-terminus of the TSC2 protein is involved in tumor suppression (PMID: 8799170, 17379185). For these reasons, this variant has been classified as Pathogenic.

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