Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002513723 | SCV003443423 | likely pathogenic | Tuberous sclerosis 2 | 2022-02-18 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1620 of the TSC2 protein (p.His1620Arg). This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.His1620 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10533067, 16114042). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). 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. ClinVar contains an entry for this variant (Variation ID: 65243). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. |
| Tuberous sclerosis database |
RCV000055464 | SCV000083685 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation | ||
| Division of Hematology/Oncology, |
RCV000590930 | SCV000693713 | drug response | Everolimus response | 2017-01-01 | no assertion criteria provided | clinical testing | Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2-associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alteration H1620R in exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of the TSC2 gene. |