Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498705 | SCV000589791 | likely pathogenic | not provided | 2016-03-25 | criteria provided, single submitter | clinical testing | The L1066P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L1066P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same (L1066R) residue was previously reported in an individual with subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (Kwiatkowski et al, 2015), and missense variants in nearby residues (W1060R, L1061P, T1068I, T1071I) have been reported in the Human Gene Mutation Database in association with TSC (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense variants have been identified (Northrup et al., 2011; Au et al., 2007). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV002298458 | SCV002594145 | uncertain significance | Tuberous sclerosis 2 | 2022-09-23 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1066 of the TSC2 protein (p.Leu1066Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 65283). 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. 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. |
| Tuberous sclerosis database |
RCV000055504 | SCV000083727 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |