Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001053848 | SCV001218130 | uncertain significance | Tuberous sclerosis 2 | 2023-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1364 of the TSC2 protein (p.Ser1364Ala). 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: 849814). 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. Experimental studies have shown that this missense change does not substantially affect TSC2 function (PMID: 15963462, 35288456). 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 | RCV002320295 | SCV002626562 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-16 | criteria provided, single submitter | clinical testing | The p.S1364A variant (also known as c.4090T>G), located in coding exon 33 of the TSC2 gene, results from a T to G substitution at nucleotide position 4090. The serine at codon 1364 is replaced by alanine, an amino acid with similar properties. Functional analyses demonstrated that this variant does not have a significant impact on the formation of the TSC1–TSC2 complex (Nellist M et al. Biochem Biophys Res Commun, 2005 Aug;333:818-26). This amino acid position is not 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. |