Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000497895 | SCV000590319 | uncertain significance | not provided | 2018-12-17 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the TSC2 gene. The G1356V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G1356V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1356V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species. Additionally, this substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense variants have been identified (Northrup et al., 2011; Au et al., 2007). However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV000702009 | SCV000830836 | uncertain significance | Tuberous sclerosis 2 | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1356 of the TSC2 protein (p.Gly1356Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432576). 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. 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. |
Ambry Genetics | RCV001021794 | SCV001183454 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-25 | criteria provided, single submitter | clinical testing | The p.G1356V variant (also known as c.4067G>T), located in coding exon 33 of the TSC2 gene, results from a G to T substitution at nucleotide position 4067. The glycine at codon 1356 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Genome- |
RCV000702009 | SCV002040804 | uncertain significance | Tuberous sclerosis 2 | 2021-11-07 | criteria provided, single submitter | clinical testing |