Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000553605 | SCV000644601 | pathogenic | Tuberous sclerosis 2 | 2017-04-05 | criteria provided, single submitter | clinical testing | This variant has been reported in a family affected with tuberous sclerosis (TSC), and segregation with disease was stated, however details of the affected individuals other than the proband were not provided (PMID: 9829910). It has also been reported in an individual affected with TSC in the Leiden Open-source Variation Database (PMID: 21520333). Furthermore, it was found to have arisen de novo in an individual with TSC (Invitae database). ClinVar contains an entry for this variant (Variation ID: 49344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 1690 of the TSC2 protein (p.Asp1690Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant also falls at the last nucleotide of exon 39 of the TSC2 coding sequence, which is part of the consensus splice site for this exon. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, while this variant has uncertain impact on protein function, it is absent from the population and reported in affected individuals, including a de novo finding. Therefore, it has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. |
| Tuberous sclerosis database |
RCV000042604 | SCV000066398 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |