ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2087G>T (p.Cys696Phe)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285367 SCV001471785 likely pathogenic none provided 2020-03-09 criteria provided, single submitter clinical testing The TSC2 c.2087G>T; p.Cys696Phe variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 696 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two other variants at this codon (Cys696Arg, Cys696Tyr) are reported in individuals with TSC (Hung 2006, Jones 1999). Functional studies of the Cys696Tyr variant shows it inhibits tuberin-hamartin binding, the tuberin chaperone function and tuberin phosphorylation (Hoogeveen-Westerveld 2011, Nellist 2001). Based on available information, the p.Cys696Phe variant is considered to be likely pathogenic. REFERENCES Hoogeveen-Westerveld M et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. Hung CC et al. Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med Genet. 2006 Sep 18;7:72. Jones AC et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet. 1999 May;64(5):1305-15. Nellist M et al. TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Hum Mol Genet. 2001 Dec 1;10(25):2889-98.

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