Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002326765 | SCV002633807 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-01-04 | criteria provided, single submitter | clinical testing | The p.L1584R variant (also known as c.4751T>G), located in coding exon 36 of the TSC2 gene, results from a T to G substitution at nucleotide position 4751. The leucine at codon 1584 is replaced by arginine, an amino acid with dissimilar properties. Functional assessment of the p.L1584R variant demonstrated TSC1 and TSC2 signals not significantly different from wild-type; however, the mean T389/S6K ratio was significantly higher than that of wild-type TSC2 indicating reduced TSC1-TSC2-dependent inhibition of TORC1 activity (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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV002514176 | SCV003443420 | likely pathogenic | Tuberous sclerosis 2 | 2022-05-30 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1584 of the TSC2 protein (p.Leu1584Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 22903760; Invitae). ClinVar contains an entry for this variant (Variation ID: 50096). 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). 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. |
| Tuberous sclerosis database |
RCV000043362 | SCV000067168 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |