Submissions for variant NM_000548.5(TSC2):c.4784G>A (p.Gly1595Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003039214	SCV003333411	likely pathogenic	Tuberous sclerosis 2	2022-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1595 of the TSC2 protein (p.Gly1595Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (TSC) (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. This variant disrupts the p.Gly1595 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31927531; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV003170912	SCV003859971	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	The p.G1595E variant (also known as c.4784G>A), located in coding exon 36 of the TSC2 gene, results from a G to A substitution at nucleotide position 4784. The glycine at codon 1595 is replaced by glutamic acid, an amino acid with similar properties. Internal structural analysis indicates that this variant disrupts a motif known to be involved in GAP-Rheb binding-specificity (Ambry internal data; Yang H et al. Nat Commun, 2021 Jan;12:339; Hansmann P et al. Structure, 2020 Aug;28:933-942.e4; Inoki K et al. Genes Dev, 2003 Aug;17:1829-34). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.