Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000685864 | SCV000813364 | uncertain significance | Tuberous sclerosis 2 | 2023-03-16 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 21520333). 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. 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. ClinVar contains an entry for this variant (Variation ID: 566128). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1668 of the TSC2 protein (p.Phe1668Leu). |
| Ambry Genetics | RCV002334252 | SCV002644530 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-13 | criteria provided, single submitter | clinical testing | The p.F1668L variant (also known as c.5004T>G), located in coding exon 38 of the TSC2 gene, results from a T to G substitution at nucleotide position 5004. The phenylalanine at codon 1668 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in the literature in an individual with cortical dysplasia, but no additional features of Tuberous Sclerosis were identified (Hansmann P et al. Structure, 2020 08;28:933-942.e4). In vitro functional studies indicated that this variant inhibits GAP catalytic activity, but retains the ability to inhibit mTORC activity (Hansmann P et al. Structure, 2020 08;28:933-942.e4). The clinical impact of these findings is not clear. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |