ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.736A>G (p.Thr246Ala)

gnomAD frequency: 0.00002  dbSNP: rs137854123
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554931 SCV000644664 likely benign Tuberous sclerosis 2 2024-01-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000612409 SCV000711361 uncertain significance not specified 2016-09-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr246Ala variant in TSC2 has been reported in 1 Asian individual as well as one family m ember with Tuberous Sclerosis (Sasongko 2008). This variant has been identified in 1/10372 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs137854123). Computational prediction tools and conservation analysis suggest that the p.Thr246Ala variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr246Ala variant is uncertain.
Genome-Nilou Lab RCV000554931 SCV002041093 likely benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
GeneDx RCV002288539 SCV002578860 uncertain significance not provided 2022-09-30 criteria provided, single submitter clinical testing Previously reported as a maternally inherited variant of uncertain significance in a patient suspected to have TSC; detailed clinical information not provided (Meng et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18466115, 26994145, 30564305, 18772611, 32917966, 25637381)
Ambry Genetics RCV002381326 SCV002670443 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-12 criteria provided, single submitter clinical testing The p.T246A variant (also known as c.736A>G), located in coding exon 7 of the TSC2 gene, results from an A to G substitution at nucleotide position 736. The threonine at codon 246 is replaced by alanine, an amino acid with similar properties. This alteration was detected in two members of a Japanese family with features of tuberous sclerosis (TSC) (Sasongko TH et al, 2008 May;54:E73-81). This alteration was identified in 1/374 Chinese patients with clinically suspected TSC undergoing genetic testing within the TSC1 and TSC2 genes, and was classified as a variant of unknown significance by the authors (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003460556 SCV004204529 uncertain significance Isolated focal cortical dysplasia type II 2023-10-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000042644 SCV004817017 uncertain significance Tuberous sclerosis syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 246 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with tuberous sclerosis complex (PMID: 18772611). This variant has been identified in 4/249706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Tuberous sclerosis database (TSC2) RCV000042644 SCV000066439 not provided Tuberous sclerosis syndrome no assertion provided curation
CSER _CC_NCGL, University of Washington RCV000042644 SCV000190674 uncertain significance Tuberous sclerosis syndrome 2014-06-01 no assertion criteria provided research

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