ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.2208+2T>A (rs1064794132)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565398 SCV000664763 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
GeneDx RCV000487211 SCV000567931 pathogenic not provided 2015-09-16 criteria provided, single submitter clinical testing The c.2208+2T>A variant in the TSC1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 17. 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.2208+2T>A 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. We interpret c.2208+2T>A as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000781918 SCV000920329 likely pathogenic Tuberous sclerosis syndrome 2018-03-06 criteria provided, single submitter clinical testing Variant summary: TSC1 c.2208+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was absent in 245912 control chromosomes. To our knowledge, no occurrence of c.2208+2T>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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