TABLE 1.
Impact of retrospective reassessment of variant pathogenicity. (A) Reclassification/prioritisation of variants according to CE/EF scores. (B) Prioritization of variants in genes with mis_z > 3 or pLI >0.9 according to gnomAD.
| (A) Reclassification/prioritisation of variants according to CE/EF scores. | (B) Prioritization of variants in genes with mis_z > 3 or pLI >0.9 according to gnomAD. | |||||||
|---|---|---|---|---|---|---|---|---|
| CM Subtype | No. of genes with CE | No. of patients with LP/P variants according to RDC (no. of variants) | (i) | (ii) Analyses of VUS | No. of patients without genetic diagnosis, but variants (VUS) leading to definitive reclassification to LP | No. of patients | ||
| No of patients with LP/p variants according to CE/EF scores (no. of variants) | Correlation of variant classification between RDC and CE/EF scores | No. of patients with prioritised variants because of CE | No. of patients without genetic diagnosis, but variants possibly leading to reclassification | |||||
| HCM | 14 | 169 (172) | 158 (160) | 93% | 61 | 44 | 19 | — |
| DCM | 14 | 181 (186) | 178 (177) | 95% | 55 | 46 | 6 | 2 |
| ACM | 5 | 19 (20) | 17 (17) | 85% | 1 | 1 | — | — |
| CM | — | — | — | — | 26 | 22 | — | 11 |
| LVNC | — | — | — | — | — | — | — | 6 |
| TOTAL | 33 | 369 (378) | 353 (354) | 94% | 143 | 113 | 25 | 19 |
| No. of patients with selected variants | — | — | — | — | 113 (6%) | 25 (1.2%) | 19 (1%) | |
A) 1) Variants classified as (L)P following RDC, CE/EF criteria and their correlations, 2) patients identified, after application of CE/EF scores on VUSs in CM subtype-specific genes, with reclassified variants and/or variants prioritized for future functional and/or co-segregation studies. B) Additional VUSs prioritized of genes not yet addressed within the CE/EF approach and having significant missense Z (mis_z) and/or probability of loss-of-function intolerant (pLI) scores adapted from the genome aggregation (gnomAD) database.