Submissions for variant NM_000548.5(TSC2):c.4846C>T (p.Gln1616Ter)

dbSNP: rs45455296

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470698	SCV000544319	pathogenic	Tuberous sclerosis 2	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1616*) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 16981987). ClinVar contains an entry for this variant (Variation ID: 49326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091866	SCV001248123	pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000470698	SCV002041006	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001091866	SCV002770201	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32055024, 16981987)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001091866	SCV003800460	pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	The TSC2 c.4846C>T; p.Gln1616Ter variant (rs45455296) is reported in the literature in an individual affected with tuberous sclerosis (Hung 2006). This variant is reported in ClinVar (Variation ID: 49326) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro and in vivo functional analyses demonstrate that loss of the TSC2 GAP domain function, where the p.Gln1616Ter variant lies, prevents TSC2 activity (Fu 2013, Hansmann 2020). Additionally, upstream and downstream truncating variants have been described in individuals with tuberous sclerosis and are considered to be pathogenic (Maheshwar 1997). Based on available information, this variant is considered to be pathogenic. References: Fu C et al. Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. Genesis. 2013 Apr;51(4):284-92. PMID: 23359422 Hansmann P et al. Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations. Structure. 2020 Aug 4;28(8):933-942.e4. PMID: 32502382 Hung CC et al. Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med Genet. 2006 Sep 18;7:72. PMID: 16981987 Maheshwar MM et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet. 1997 Oct;6(11):1991-6. PMID: 9302281
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000470698	SCV004806093	uncertain significance	Tuberous sclerosis 2	2024-03-25	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042586	SCV000066380	not provided	Tuberous sclerosis syndrome		no assertion provided	curation