Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion, |
RCV002051805 | SCV002318678 | likely pathogenic | Tuberous sclerosis 2 | 2024-07-30 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v4.0.0 dataset. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with TSC2 related disorder (PMID: 28074849). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 28074849 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 28074849). A different missense change at the same codon (p.Leu733Pro) has been reported to be associated with TSC2-related disorder (ClinVar ID: VCV000050119 / PMID: 10942116). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV002051805 | SCV003443061 | pathogenic | Tuberous sclerosis 2 | 2022-04-16 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 733 of the TSC2 protein (p.Leu733Val). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 28074849). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu733 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID: 10942116), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 65222). |
| Tuberous sclerosis database |
RCV000055442 | SCV000083663 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |