Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000457139 | SCV000544426 | pathogenic | Tuberous sclerosis 2 | 2022-05-03 | criteria provided, single submitter | clinical testing | Studies have shown that this variant results in a splicing defect and introduces a premature termination codon (PMID: 10533066, 11068191). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 49923). This variant is also known as IVS8+281C>T. This variant has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 10533066, 26540169; 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). This sequence change falls in intron 9 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. |
Centre for Mendelian Genomics, |
RCV001197516 | SCV001368292 | pathogenic | Lymphangiomyomatosis | 2018-12-21 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1. |
Centogene AG - |
RCV000457139 | SCV001426479 | pathogenic | Tuberous sclerosis 2 | criteria provided, single submitter | clinical testing | ||
Genome- |
RCV000457139 | SCV002040924 | pathogenic | Tuberous sclerosis 2 | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Gene |
RCV002243690 | SCV002512895 | pathogenic | not provided | 2021-07-23 | criteria provided, single submitter | clinical testing | Non-canonical splice site variant demonstrated to result in loss-of-function; RNA studies indicate the variant activates a cryptic splice donor site in intron 9, leading to the addition of incorrect amino acids and an additional stop codon in exon 10 (Mayer et al., 1999; Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19823873, 10533066, 11068191, 32860008, 26540169) |
Ambry Genetics | RCV002444498 | SCV002680816 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-20 | criteria provided, single submitter | clinical testing | The c.848+281C>T intronic pathogenic mutation results from a C to T substitution 281 nucleotides after coding exon 8 in the TSC2 gene. This mutation has been detected twice, once as a de novo occurrence, in individuals meeting diagnostic criteria for tuberous sclerosis complex (TSC) (Mayer K et al. Hum. Mutat., 1999;14:401-11; Tyburczy ME et al. PLoS Genet., 2015 Nov;11:e1005637). Functional studies performed at the RNA level showed this mutation creates a cryptic splice donor site that leads to the structural functionality of intron 8, resulting in the incorporation of a pseudoexon between exons 8 and 9, and ultimately resulting in a frameshift and premature protein truncation (Mayer K et al. Biochim. Biophys. Acta, 2000 Nov;1502:495-507). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Tuberous sclerosis database |
RCV000043190 | SCV000066991 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |