Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001042713 | SCV001206413 | pathogenic | Tuberous sclerosis 2 | 2019-11-22 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with tuberous sclerosis complex (Invitae, Leiden Open-source Variation Database (PMID: 21520333)). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50058). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1095 of the TSC2 protein (p.Ser1095Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 28 of the TSC2 coding sequence, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002321537 | SCV002607009 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2017-08-15 | criteria provided, single submitter | clinical testing | The p.S1095N variant (also known as c.3284G>A), located in coding exon 27 of the TSC2 gene, results from a G to A substitution at nucleotide position 3284. This change occurs in the last base pair of coding exon 27, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the serine at codon 1095 to asparagine, an amino acid with highly similar properties. In one study, this alteration was detected as a de novo occurrence in an individual with a clinical diagnosis of tuberous sclerosis complex (TSC) (Au KS et al. Genet. Med., 2007 Feb;9:88-100). This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV003313034 | SCV004012641 | likely pathogenic | not provided | 2023-01-06 | criteria provided, single submitter | clinical testing | Reported previously as a probably pathogenic variant in a cohort of patients with autism spectrum disorder; however, no further clinical or segregation information was provided (Bahl et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Variant in the last nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23514105, 32917966, 17304050, 32461669) |
| Tuberous sclerosis database |
RCV000043324 | SCV000067130 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |