Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000699092 | SCV000827787 | likely pathogenic | Tuberous sclerosis 1 | 2018-03-05 | criteria provided, single submitter | clinical testing | 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. This sequence change affects an acceptor splice site in intron 20 of the TSC1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with TSC1-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). |
| Ambry Genetics | RCV003163230 | SCV003854585 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-12-30 | criteria provided, single submitter | clinical testing | The c.2626-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 19 in the TSC1 gene. This alteration has been identified in a tuberous sclerosis complex (TSC) cohort (Ng SY et al. Eur J Med Genet, 2022 Oct;65:104573). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic. |
| Laboratory for Molecular Medicine, |
RCV004017720 | SCV004848143 | pathogenic | Tuberous sclerosis syndrome | 2017-12-05 | criteria provided, single submitter | clinical testing | The c.2626-2A>C variant in TSC1 has not been reported in individuals with tuberous sclerosis (TSC) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Another nucleotide change at this position (c.2626-2A>G) has been reported in an individual with TSC (Au 2007), supporting that variation at position c.2626-2 leads to loss of TSC1 function. Heterozygous loss-of-function of the TSC1 gene is an established disease mechanism in individuals with tuberous sclerosis. In summary, this variant meets our criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PM5; PM2. |