Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001238557 | SCV001411376 | pathogenic | Tuberous sclerosis 2 | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1642 of the TSC2 protein (p.Gly1642Asp). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 49978). This variant is also known as G1619D. This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 22867869, 28087349, 30024541, 34489640; 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). |
| Ambry Genetics | RCV002345329 | SCV002646412 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-20 | criteria provided, single submitter | clinical testing | The p.G1642D pathogenic mutation (also known as c.4925G>A), located in coding exon 37 of the TSC2 gene, results from a G to A substitution at nucleotide position 4925. The glycine at codon 1642 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in individuals with a clinical diagnosis of tuberous sclerosis (Gao S et al. Medicine (Baltimore), 2018 Jul;97:e11533; Ismail NF et al. J Mol Diagn, 2017 03;19:265-276; van Eeghen AM et al. Epilepsy Res., 2013 Jan;103:83-7; Ambry internal data). A functional analysis of this alteration using a transfection-based immunoblot assay indicated the T389/S6K ratio was significantly higher compared to wildtype TSC1-TSC2, and was therefore interpreted as pathogenic. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998143 | SCV005622724 | pathogenic | not provided | 2024-05-08 | criteria provided, single submitter | clinical testing | The TSC2 c.4925G>A (p.Gly1642Asp) variant has been reported in the published literature in multiple tuberous sclerosis patients (PMID: 30024541 (2018), PMID: 32555378 (2020)), including those with features such as infantile spasms (PMID: 22867869 (2013)), focal epilepsy (PMID: 34489640 (2021)), cortical tubers, confetti skin lesions, and cardiac rhabdomyomas (PMID: 28087349 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. |
| Tuberous sclerosis database |
RCV000043245 | SCV000067046 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |