Submissions for variant NM_000548.5(TSC2):c.2092A>G (p.Lys698Glu)

dbSNP: rs796053510

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190070	SCV000243745	uncertain significance	not provided	2014-10-13	criteria provided, single submitter	clinical testing	p.Lys698Glu (AAG>GAG): c.2092 A>G in exon 19 of the TSC2 gene (NM_000548.3) A variant of unknown significance has been identified in the TSC2 gene. The K698E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K698E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, it is less conserved in distantly related species in evolution. Multiple missense mutations in nearby residues have been reported in association with tuberous sclerosis, supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in TUBSC-EPIV2 panel(s).
Invitae	RCV001317178	SCV001507827	uncertain significance	Tuberous sclerosis 2	2020-10-15	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt TSC2 protein function. This variant has not been reported in the literature in individuals with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 207781). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 698 of the TSC2 protein (p.Lys698Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid.
Genome-Nilou Lab	RCV001317178	SCV002040677	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing