Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000473316 | SCV000544408 | pathogenic | Tuberous sclerosis 2 | 2022-01-12 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Tyr598 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21309039, 21520333). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 598 of the TSC2 protein (p.Tyr598Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with tuberous sclerosis complex (TSC) (PMID: 21520333, 22903760; Invitae). ClinVar contains an entry for this variant (Variation ID: 50162). 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. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004948152 | SCV005527850 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-09-13 | criteria provided, single submitter | clinical testing | The p.Y598C pathogenic mutation (also known as c.1793A>G), located in coding exon 16 of the TSC2 gene, results from an A to G substitution at nucleotide position 1793. The tyrosine at codon 598 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with tuberous sclerosis complex (Ambry internal data; Milon V et al. Eur J Hum Genet, 2024 May; Kwiatkowski DJ et al. Eur J Hum Genet, 2015 Dec;23:1665-72). In one functional study, this alteration was found to have intermediate loss of the TSC1-TSC2 dependent inhibition of TORC1 (Hoogeveen-Westerveld M et al. Hum Mutat, 2013 Jan;34:167-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Tuberous sclerosis database |
RCV000043430 | SCV000067236 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |