Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002326760 | SCV002635375 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-02-01 | criteria provided, single submitter | clinical testing | The p.P1497R pathogenic mutation (also known as c.4490C>G), located in coding exon 33 of the TSC2 gene, results from a C to G substitution at nucleotide position 4490. The proline at codon 1497 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in at least twice, once as a de novo occurrence, in individuals with definite diagnoses of tuberous sclerosis (TSC) (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15; van Eeghen AM et al. Eur. J. Hum. Genet., 2012 May;20:510-5). In another study, authors used a transfection-based immunoblot assay which showed that this mutation exhibited significantly higher phoshorylation levels compared to wildtype TSC2, and was therefore interpreted as pathogenic (Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV003511986 | SCV004296673 | pathogenic | Tuberous sclerosis 2 | 2022-11-26 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Pro1497 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24271014, 28643795, 31655562; Invitae). 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: 21309039). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 49491). This variant is also known as P1474R. This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 10205261, 22189265; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1497 of the TSC2 protein (p.Pro1497Arg). For these reasons, this variant has been classified as Pathogenic. |
| Tuberous sclerosis database |
RCV000042751 | SCV000066546 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |