Tuberous sclerosis complex (TSC) is a rare genetic disease caused by heterozygous dominant mutations in the TSC1 or TSC2 genes that affects 1/6000 newborns (Curatalo et al., 2002; de Vries & Howe, 2007). TSC has a variety of clinical manifestations ranging from hypomelanotic macules to neurological conditions such as epilepsy (Neuman & Henske, 2011; de Vries & Howe, 2007). In cases where the TSC mutations are inherited from parent to offspring (familial TSC)- the child can still exhibit more severe symptoms despite having the same TSC mutation as the parent, a phenomenon known as intrafamilial phenotypic variability (IPV) (Curatalo et al, 2002). We hypothesize that the variants in genes of the mTOR signaling pathway (genetic modifiers) may enhance or suppress mTOR pathway activity, resulting in IPV. Patient derived primary fibroblasts cell lines from two families exhibiting IPV were studied as well as an unrelated control cell line. We identified variants in IRS1, FZD5, and PIK32CG genes from children with severe phenotype in one family and variants in PIK3R3, TNFRSF19, and EIF4G1 in a severe child in another pathway. We explored the functional impact of these genes on mTOR pathway activity.