Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657472 | SCV000779207 | uncertain significance | not provided | 2018-02-14 | criteria provided, single submitter | clinical testing | This deletion of four nucleotides in exon 26 of TSC2 is denoted c.2892_2895delAGAA at the cDNA level and p.Lys964AsnfsX51 (K964NfsX51) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGAA[delAGAA]TTCA. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 964, and creates a premature stop codon at position 51 of the new reading frame. Although this variant is predicted to cause loss of normal protein function, current evidence indicates that variants in exon 26 (referred to as exon 25 by alternate numbering) are unlikely to cause tuberous sclerosis (TS) (Ekong 2016). Specifically, loss-of-function variants in this exon have been identified in the published literature and at GeneDx in individuals who do not have features of TS (Ekong 2016). RNA expression analysis demonstrates an abundance of transcripts lacking this exon in multiple normal tissue types from healthy adults, and in vitro studies indicate that this exon is not essential for normal functional activity of the TSC complex (Ekong 2016). TSC2 c.2892_2895delAGAA was not observed in large population cohorts (Lek 2016). This variant has not, to our knowledge, been reported in the literature. Based on currently available evidence, it is unclear whether TSC2 c.2892_2895delAGAA is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |