Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000548.5(TSC2):c.410A>G(p.His137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 10570911). ClinVar contains an entry for this variant (Variation ID: 49283). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 137 of the TSC2 protein (p.His137Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. -
Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);Gain of phosphorylation at S132 (P = 0.1135);.;