Targeted Genomic Sequencing of TSC1 and TSC2 Reveals Causal Variants in Individuals for Whom Previous Genetic Testing for Tuberous Sclerosis Complex Was Normal
Table 3
TSC1 and TSC2 variants of uncertain clinical significance (VUS), lesion-specific variants, and unconfirmed findings identified using HaloPlex custom capture NGS. Individuals fulfilling the clinical criteria for definite TSC [3] are indicated with “TSC”; those fulfilling only criteria for possible TSC are indicated with “?.” VAF: variant allele frequency, refers to the proportion of reads containing the corresponding variant. Cases for which multiple DNA samples or family members were tested are indicated. Evidence for effects on pre-mRNA splicing was obtained by analysis of subject RNA isolated from peripheral blood (RNA1.) and/or by in vitro exon trap assay (RNA3; see Supplementary Information Tables S7 and S8). ClinVar, Leiden Open Variation Database (LOVD), and gnomAD were accessed on 13/2/2023. P: pathogenic; LP: likely pathogenic; VUS: variant of uncertain clinical significance; LB: likely benign. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria [15] using the ALAMUT Visual Plus (version 1.7) software package. Individuals 3.23-3.72 remained NMI after HaloPlex analysis (see Supplementary Information, Table S6).
Missense; functional study (LOVD); 4 x ClinVar; 15 Mb deletion identified in DNA isolated from Shagreen patch, VAF ~15% (E. Legius, personal communication)
