TSC2, which encodes the protein tuberin, was first reported in relation to autosomal dominant tuberous sclerosis complex (TSC) in 1993 (European Chromosome 16 tuberous Sclerosis Consortium PMID: 8269512). Numerous variants have been reported in TSC2 in relation to tuberous sclerosis complex, including missense, nonsense, indels and small deletions that result in frameshift, as well as intragenic deletions (Hasbani and Crino, 2018 PMID: 29478616). The TSC2 database in LOVD (http://chromium.lovd.nl/LOVD2/TSC/home.php?select_db=TSC2) shows a total of 2689 unique variants associated with TSC2 (as of Jan 07, 2019). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for 20 years, therefore a significant amount of case-level data is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by functional studies including expression and protein interaction and animal models. The molecular mechanism for TSC2 in tuberous sclerosis is loss of function, as indicated by deletion and nonsense variation, as well as biochemical loss of tumor suppressor activity (Hasbani and Crino, 2018 PMID: 29478616). In summary, TSC2 is DEFINITIVELY associated with autosomal dominant tuberous sclerosis complex. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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