Table 2. Characterization of 606 Germline and 504 Somatic RB1 Pathogenic Variants From 854 Retinoblastoma (RB) Probands.
| Pathogenic variant type | No. (%) | ||||||
|---|---|---|---|---|---|---|---|
| Germline pathogenic variants | Somatic pathogenic variants | Total identified pathogenic variants (n = 1110) | |||||
| Unilateral (n = 109) | Bilateral (n = 497) | Total (n = 606) | Unilateral (n = 484) | Bilateral (n = 20) | Total (n = 504) | ||
| Presence of RB protein | |||||||
| Missense | 13 (11.9) | 12 (2.4) | 25 (4.1) | 2 (0.4) | 0 | 2 (0.4) | 27 (2.4) |
| In-frame deletion | 1 (0.9) | 3 (0.6) | 4 (0.7) | 2 (0.4) | 0 | 2 (0.4) | 6 (0.5) |
| Splice pathogenic variant in frame, exonic | 0 | 2 (0.4) | 2 (0.3) | 1 (0.2) | 0 | 1 (0.2) | 3 (0.3) |
| Splice pathogenic variant in frame, intronic | 8 (7.4) | 25 (5.1) | 33 (5.5) | 7 (1.4) | 0 | 7 (1.4) | 40 (3.6) |
| Promoter methylation | 0 | 0 | 0 | 27 (5.4) | 0 | 27 (5.3) | 27 (2.4) |
| Promoter sequence pathogenic variants | 2 (1.8) | 3 (0.6) | 5 (0.8) | 1 (0.2) | 0 | 1 (0.2) | 6 (0.5) |
| Total | 24 (22.0) | 45 (9.1) | 69 (11.4) | 40 (8.0) | 0 | 40 (7.9) | 109 (9.8) |
| Absence of RB protein | |||||||
| Frameshift deletion | 20 (18.4) | 90 (18.1) | 110 (18.2) | 43 (8.9) | 1 (5.0) | 44 (8.7) | 154 (13.9) |
| Frameshift delinsa | 0 | 0 | 0 | 1 (0.2) | 0 | 1 (0.2) | 1 (0.1) |
| Frameshift insertion | 5 (4.6) | 25 (5.0) | 30 (4.8) | 12 (2.5) | 0 | 12 (2.4) | 42 (3.8) |
| Nonsense | 24 (22.0) | 198 (39.8) | 222 (36.6) | 118 (24.5) | 6 (30.0) | 124 (24.6) | 346 (31.2) |
| Large rearrangementb | 17 (15.6) | 48 (9.7) | 65 (10.8) | 45 (9.4) | 1 (5.0) | 46 (9.1) | 111 (10.0) |
| Loss of heterozygosityc | 0 | 0 | 0 | 194 (40.1) | 11 (55.0) | 205 (40.7) | 205 (18.5) |
| Splice out of frame, exonic | 1 (0.9) | 10 (2.0) | 11 (1.8) | 2 (0.4) | 0 (0) | 2 (0.4) | 13 (1.2) |
| Splice out of frame, intronic | 18 (16.5) | 81 (16.3) | 99 (16.4) | 29 (6.0) | 1 (5.0) | 30 (6.0) | 129 (11.6) |
| Total | 85 (78.0) | 452 (90.9) | 537 (88.6) | 444 (92.0) | 20 (100) | 464 (92.1) | 1001 (90.2) |
a
Described as a variant event combining deletion and insertion at the same time.
b
Large deletions or duplications from a single exon to the entire gene.
c
Loss of the wild-type allele by different mechanisms (ie, deletions with or without duplication of the mutant allele or mitotic recombination [second hit]).