A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation.

Tuberous sclerosis (TSC) is an autosomal dominant hamartoma syndrome due to mutations in either TSC1 or TSC2. Previous reports have identified a mutation consisting of a 34 bp deletion affecting portions of exon 38 and the adjacent intron 38 of TSC2. We found this genetic variation in 4 of 800 TSC patients screened for mutations in TSC1 and TSC2. In every case, the variant was present in one unaffected parent of the sporadically affected TSC child. By RT-PCR analysis of RNA samples from two additional families with this genetic variant, we demonstrate that the allele with the deletion generates about 50% normal RNA transcript, and 50% RNA transcript including intron 38. In addition, there is no correlation between the extent of splicing and clinical status of family members. We also excluded the possibility of mosaicism in the parents with this variant. We conclude that this deletion is a rare polymorphism that does not cause TSC, but may be a modifier of the TSC phenotype.