Table 2.
Genetic variants class III-V in CTEPH patients identified by next generation sequencing (NGS).
| Gene | RefSeq ID | Exon | c.DNA | Protein | n | Classification * | Prediction Programmes | CADD Score | gnomAD (n) |
|---|---|---|---|---|---|---|---|---|---|
| BMPR2 | NM_001204 | 12 | c.2071A>T | p.(Lys691*) | 1 | Pathogenic variant (class V) |
NA (nonsense) | 38.0 | 0 |
| JAK2 | NM_001322194 | 14 | c.1849G>T # | p.(Val617Phe) | 3 | Pathogenic variant (class V) |
gain-of-function | 31.0 | 97 |
| BMPR1B | NM_001203 | 8 | c.556T>A | p.(Ser186Thr) | 1 | VUS (class III) | 3/4 pathogenic | 23.6 | 3 |
| BTNL2 | NM_001304561 | 4 | c.710-4_710-8 delinsCGCTC | intronic | 1 | VUS (class III) | NA (intronic) | NA | 0 |
| CYP1B1 | NM_000104 | 2 | c.164T>G | p.(Phe55Cys) | 1 | VUS (class III) | 2/4 pathogenic | 22.1 | 1 |
| IL6 | NM_000600 | 3 | c.263A>G | p.(Asn88Ser) | 1 | VUS (class III) | 4/4 pathogenic | 22.4 | 3 |
| JAK2 | NM_001322194 | 24 | c.3188G>A | p.(Arg1063His) | 1 | VUS (Class III) | 2/4 pathogenic | 24.8 | 1272 |
| KCNA5 | NM_002234 | 1 | c.213_245del | p.(Asp72_Pro82del) | 1 | VUS (Class III) | NA (in frame deletion) | NA | 147 |
| NOTCH3 | NM_000435 | 1 | c.30_35dup | p.(Arg12ArgArgArg) | 1 | VUS (class III) | NA (in frame duplication) | NA | 0 |
| SMAD4 | NM_005359 | 5 | c.565C>T | p.(Arg189Cys) | 1 | VUS (class III) | 3/4 pathogenic | 23.6 | 99 |
| SMAD6 | NM_005585 | 1 | c.538C>G | p.(Leu189Val) | 1 | VUS (class III) | 3/4 pathogenic | 25.3 | 1 |
| TOPBP1 | NM_007027 | 14 | c.2456A>C | p.(His819Pro) | 1 | VUS (class III) | 1/4 pathogenic | 20.9 | 0 |
# Same somatic variant identified in three unrelated patients; * Variants were characterised following guidelines from the American College of Medical Genetics and Genomics [30]; Prediction programmes used: align Grantham variation Grantham deviation (Align-GVGD), sorting intolerant from tolerant (SIFT), PolyPhen2 and MutationTaster; Abbreviations: CADD: combined annotation dependent depletion, c.DNA: coding DNA, CTEPH: chronic thromboembolic pulmonary hypertension, gnomAD: genome aggregation database with 141.456 reported sequences, n: number of CTEPH patients with the variant, NA: not applicable, RefSeq ID: reference sequence identification number, VUS: variant of uncertain significance.