Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000201152 | SCV000255887 | pathogenic | Tuberous sclerosis 2 | 2012-07-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000201152 | SCV000765936 | pathogenic | Tuberous sclerosis 2 | 2023-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 889 of the TSC2 protein (p.Ala889Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with tuberous sclerosis complex (PMID: 21309039, 21520333, 30185235; Invitae). ClinVar contains an entry for this variant (Variation ID: 49586). 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. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). This variant disrupts the p.Ala889 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Genome- |
RCV000201152 | SCV002039675 | likely pathogenic | Tuberous sclerosis 2 | 2021-11-07 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002433527 | SCV002744844 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-14 | criteria provided, single submitter | clinical testing | The p.A889V variant (also known as c.2666C>T), located in coding exon 23 of the TSC2 gene, results from a C to T substitution at nucleotide position 2666. The alanine at codon 889 is replaced by valine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC-related disease (Ambry internal data; Invitae pers. comm.; Liu J et al. Mol Brain, 2018 09;11:48). A protein functional assay using a transfection-based immunoblot assay determined this alteration to be deleterious to protein function (Hoogeveen-Westerveld M et al. Hum Mutat, 2011 Apr;32:424-35). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Tuberous sclerosis database |
RCV000042847 | SCV000066643 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |