Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000688733 | SCV000816356 | uncertain significance | Tuberous sclerosis 2 | 2018-03-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 505 of the TSC2 protein (p.Arg505Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376285784, ExAC 0.01%). This variant has been reported in an individual with intellectual disability, seizures, and autistic spectrum disorder, but did not fulfill diagnostic criteria for tuberous sclerosis complex. This variant was also found in two relatives, one with mild intellectual disability and one without apparent phenotypic abnormalities (PMID: 21407264). ClinVar contains an entry for this variant (Variation ID: 64996). Experimental studies have shown that this missense change results in a partial loss of protein function. Functional assays revealed the variant results in reduced TSC1 and TSC2 protein levels, reduced binding to TSC1, increased 4E-BP1 phosphorylation levels, increased transcriptional activity of HIF-1-alpha, and an increased T389/S6K ratio compared to wild-type TSC2. However, these changes are intermediate in comparison with a pathogenic TSC2 variant (PMID: 21407264, 22903760). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Tuberous sclerosis database |
RCV000055200 | SCV000083418 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |