ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.337-1G>A (rs45517105)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518372 SCV000615899 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing
Invitae RCV000553650 SCV000644432 pathogenic Tuberous sclerosis 2 2017-08-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the TSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with tuberous sclerosis complex (TSC) (PMID: 23389244). This variant is also known as IVS3-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 65038). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.337-1G>T) has been reported in an individual affected with TSC (PMID: 10735580). This suggests that this nucleotide is important for normal RNA splicing, and that variants at this position may be pathogenic. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000055243 SCV000083462 not provided Tuberous sclerosis syndrome no assertion provided curation

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