Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000442086 | SCV000520928 | likely pathogenic | not provided | 2016-07-06 | criteria provided, single submitter | clinical testing | The R190P variant that is likely pathogenic has been identified in the TSC1 gene. Functional studiessuggest that the R190P variant results in decreased levels of TSC1 protein, reduced inhibition ofmTOR activity, and an abnormal intracellular localization pattern (Mozaffari et al., 2009). It was notobserved in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R190P variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a position that is conserved across species, and missense variants in a nearbyresidue (L191H, L191R) have been reported in the Human Gene Mutation Database in associationwith TSC (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to theprotein structure/function. However, the vast majority of TSC1 pathogenic variants result in proteintruncation, while missense variants have been reported only rarely (Northrup et al., 2011; Au et al.,2007). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot beexcluded. |
| Tuberous sclerosis database |
RCV000042311 | SCV000066100 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |