Table 1.
Functional study outcomes and sequence variant classification.
| Family (diagnosis) | Variant | MES/ADA RF/SpliceAI |
ClinVar ID (class) | Functional study outcome | ACMG classification without RNA analysis | ACMG classification with RNA analysis | Change in classification |
|---|---|---|---|---|---|---|---|
| 014 (LQTS) | KCNQ1 c.477+5 G > A |
−5.37/0.99 0.97/0.23 |
53047 (P) | Exon 2 skipped (PTC) | VUS (PS4_moderate, PM2, PP1, PP3) | LP (PS3, PS4_moderate, PM2, PP1) | VUS → LP |
| 015 (LQTS) |
KCNQ1 c.781 G > A |
1.81/0.91 0.61/0.76 |
53103 (VUS) | Exon 6 skipped (in-frame deletion) | VUS (PM2, PS4_supporting, PP3) | VUS (PM2, PM4, PS4_supporting) | No change (VUS) |
| 051 (HCM) |
MYBPC3 c.1224-80 G > A |
7.96/NA NA/0.94 |
693982 (-) | Exon 14 extension (in-frame insertion) | VUS (PS4, PP3) | LP (PS4, PM2, PM4) | VUS → LP |
| 054 (HCM) |
MYBPC3 c.1458-7 C > A |
−3.93/0.99 0.45/0.99 |
– | Exon 17 extension (PTC) | VUS (PM2, PP3) | LP (PS3, PM2) | VUS → LP |
| 102 (CPVT) |
RYR2 c.848+1 G > A |
−8.18/1.0 0.94/0.74 |
201371 (Conflicting) | Exon 11 skipped (in-frame deletion) | LP (PP1_strong, PM2, PS4_supporting) | LP (PP1_strong, PM2, PM4, PS4_supporting) | No change (LP) |
| 125 (SUD) |
TTN c.63793 G > A |
−4.57/1.0 0.99/0.74 |
202779 (VUS) | Intron retention (PTC) | LP (PP1_moderate, PM2, PS4_supporting, PP3) | LP (PS3, PP1_moderate, PM2, PS4_supporting) | No change (LP) |
ACMG/AMP critieria: PS4 - ≥ 15 probands of concordant phenotype; PS4_moderate - ≥ 6 probands of concordant phenotype; PS4_supporting - ≥ 2 probands of concordant phenotype; PS3 - functional evidence with out-of-frame change; PM2 - rarity in the population; PM4 - functional evidence with in-frame change; PP1_strong - ≥ 7 meiosis; PP1_moderate - ≥ 5 meiosis; PP1 - ≥ 3 meiosis; and PP3 - concordant in silico tool.
LQTS long QT syndrome, HCM hypertrophic cardiomyopathy, CPVT catecholaminergic polymorphic ventricular tachycardia, SUD sudden unexplained death, MES MaxEntScan score difference, ADA adaptive boosting, RF random forest, P pathogenic, VUS variant of uncertain significance, LP likely pathogenic, PTC premature termination codon.