Novel and reported late postzygotic CCM1, CCM2 or CCM3 loss-of-function variants in CCM tissues
| Reference | Gene | Constitutional or high-frequency variant identified in blood and/or CCM tissue* | Late postzygotic variant* | Frequency of the late postzygotic variant (%) | Familial/sporadic CCM | ||
| This report | CCM1 | c.2143-2A>G, p.(Ala715Valfs*14)† | Intron 19 | c.1038C>A, p.(Cys346*) | Exon 12¶ | 5.2–7.8 | Sporadic |
| 8 | CCM1 | c.1363C>T, p.(Gln455*) (also known as Q455X) | Exon 14 | c.1465_1498del, p.(Glu489Lysfs*9) | Exon 15§ | 0–21 | Familial |
| 9 | CCM1 | c.1363C>T, p.(Gln455*) | Exon 14 | c.1300del, p.(Val434Leufs*3) | Exon 14§ | 0–4.3 | Sporadic |
| 10 | CCM1 | c.1363C>T, p.(Gln455*) | Exon 14 | c.1271_1274del, p.(Ile424Thrfs*12) (also known as c.1270_1273del) | Exon 14§ | 11–25 | Unknown |
| 10 | CCM1 | c.1363C>T, p.(Gln455*) | Exon 14 | c.1003G>T, p.(Glu335*) | Exon 12§ | 4–6 | Unknown |
| 10 | CCM2 | Deletion of exons 2–10 | Exons 2–10 | c.55C>T, p.(Arg19*) | Exon 2§ | 6.3–27.5 | Familial |
| 10 | CCM3 | c.474+1G>A, p.? | Intron 7 | c.211dup, p.(Ser71Lysfs*5)‡ (also known as c.205-211insA) | Exon 5§ | 4.5–10.2 | Familial |
| 11 | CCM1 | c.213_214delinsAT, p.(Tyr71*) (also known as c.213_214CG>AT) | Exon 6 | c.1890G>A, p.(Trp630*) | Exon 18 | 0–5.3 | Sporadic |
| 11 | CCM1 | None | – | c.993T>G, p.(Tyr331*) and c.1159C>T, p.(Gln387*) | Exon 12§ Exon 13§ | 3.1–7.2 1.0–6.1 | Sporadic |
| 11 | CCM1 | None | – | c.1659_1688delinsTAAGCTGATAACATAGTCTG, p.(Leu554Lysfs*5) | Exon 16 | 0.4–11.9 | Sporadic |
| 11 | CCM1 | None | – | Loss of heterozygosity in a 12–18 kb region (including exons 15–18) | – | – | Sporadic |
Reference sequences: CCM1: LRG_650t1; CCM2: LRG_664t2; CCM3: LRG_651t1, transcript-specific exon and intron numbering (LRG_650t1 with exons 1–20, LRG_664t2 with exons 1–10, LRG_651t1 with exons 1–9).
*Variants are described according to the recommendations of the Human Genome Variation Society (HGVS).
†Constitutional mutation of the index case first reported in Stahl et al.18
‡The postzygotic variant was also detected in an independent tissue sample of a regrown CCM of the index patient.11
§In trans configuration was verified by sequencing of genomic DNA (rather short distance between the two variants) or by cDNA analysis (availability of high-quality RNA samples).
¶An immunohistochemical approach was used to demonstrate endothelial CCM1 inactivation on protein level. Postzygotic inframe and missense variants are listed in online supplementary table 1.
CCM, cerebral cavernous malformation.