Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001056606 | SCV001221057 | likely pathogenic | Tuberous sclerosis 2 | 2020-02-10 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine with valine at codon 493 of the TSC2 protein (p.Leu493Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 12111193, 29500070, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49161). This variant has been reported to affect TSC2 protein function (PMID: 22903760). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV003162356 | SCV003861796 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-01 | criteria provided, single submitter | clinical testing | The p.L493V variant (also known as c.1477C>G), located in coding exon 14 of the TSC2 gene, results from a C to G substitution at nucleotide position 1477. The leucine at codon 493 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in individuals with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Dufner Almeida LG et al. Hum Mutat, 2020 Apr;41:759-773; Papadopoulou A et al. Eur J Paediatr Neurol, 2018 May;22:419-426; Langkau N et al. Eur J Pediatr, 2002 Jul;161:393-402). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In one functional study, this alteration was found to have an intermediate impact on TSC1-TSC2 dependent inhibition of TORC1 compared to wild type (Hoogeveen-Westerveld M et al. Hum Mutat, 2013 Jan;34:167-75). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies showed this alteration to result in an alternate acceptor gain resulting in the deletion of 11 amino acids which functionally impaired TORC1 inhibition (Dufner Almeida LG et al. Hum Mutat, 2020 Apr;41:759-773). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Tuberous sclerosis database |
RCV000042417 | SCV000066208 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |