The table below lists the 95 rare (MAF<0.0001 in ExAC) truncating PKP2 variants identified in a cohort of 361 ARVC patients. When this rare variant frequency of 0.26316 is compared with a background population rate of 0.00076, there is a statistically significant case excess of 0.26240 (p<0.0001), which suggests that approximately 95 of these variants may be pathogenic.
| No. | Variant (CDS)▼ | Variant (Protein) | Variant Type▼ | Cases (361)▼ | OMGL class | ExAC frequency |
|---|---|---|---|---|---|---|
| 1. | c.2146-1G>C | essential splice site | 24 | Pathogenic | 0.000049 | |
| 2. | c.2197_2202delinsG | p.His733Alafs*8 | frameshift | 16 | Pathogenic | 0.000000 |
| 3. | c.2489+1G>A | essential splice site | 8 | Pathogenic | 0.000024 | |
| 4. | c.1132C>T | p.Q378X | nonsense | 3 | Pathogenic | 0.000000 |
| 5. | c.275T>A | p.L92X | nonsense | 3 | Pathogenic | 0.000000 |
| 6. | c.337-2A>T | essential splice site | 2 | Pathogenic | 0.000000 | |
| 7. | c.1999G>T | p.E667X | nonsense | 2 | Pathogenic | 0.000000 |
| 8. | c.1748_1755dup | p.Val587Thrfs*72 | frameshift | 2 | Pathogenic | 0.000000 |
| 9. | c.1237C>T | p.R413X | nonsense | 2 | Pathogenic | 0.000016 |
| 10. | c.358G>T | p.E120X | nonsense | 2 | Pathogenic | 0.000000 |
| 11. | c.1901del | p.Asn634Thrfs*22 | frameshift | 2 | Pathogenic | 0.000000 |
| 12. | c.148_151delACAG | p.Thr50SerfsX61 | frameshift | 2 | Pathogenic | 0.000000 |
| 13. | c.968_975delinsGCCTTT | p.Gln323Argfs*12 | frameshift | 1 | Pathogenic | 0.000000 |
| 14. | c.1754C>G | p.S585X | nonsense | 1 | Pathogenic | 0.000000 |
| 15. | c.1177C>T | p.Q393X | nonsense | 1 | Pathogenic | 0.000000 |
| 16. | c.2058T>A | p.Y686X | nonsense | 1 | Pathogenic | 0.000000 |
| 17. | c.1125_1132del | p.Phe376Alafs*8 | frameshift | 1 | Pathogenic | 0.000000 |
| 18. | c.1892delinsTCC | p.Tyr631Phefs*26 | frameshift | 1 | Pathogenic | 0.000000 |
| 19. | c.2509delA | p.Ser837ValfsX94 | frameshift | 1 | Pathogenic | 0.000000 |
| 20. | c.2493T>A | p.Y831X | nonsense | 1 | Pathogenic | 0.000000 |
| 21. | c.663C>A | p.Y221X | nonsense | 1 | Pathogenic | 0.000008 |
| 22. | c.1689-1G>C | essential splice site | 1 | Pathogenic | 0.000008 | |
| 23. | c.1255_1279dup | p.Asn427Ilefs*7 | frameshift | 1 | Likely Pathogenic | 0.000000 |
| 24. | c.1917_1935dup | p.Gly646* | frameshift | 1 | Pathogenic | 0.000000 |
| 25. | c.215del | p.Val72Glyfs*40 | frameshift | 1 | Pathogenic | 0.000000 |
| 26. | c.235C>T | p.R79X | nonsense | 1 | Pathogenic | 0.000000 |
| 27. | c.1063C>T | p.R355X | nonsense | 1 | Pathogenic | 0.000008 |
| 28. | c.356dup | p.Tyr119* | frameshift | 1 | Pathogenic | 0.000000 |
| 29. | c.1171_1378del | p.Val391Thrfs*6 | frameshift | 1 | Likely Pathogenic | 0.000000 |
| 30. | c.1170+1G>C | essential splice site | 1 | Pathogenic | 0.000000 | |
| 31. | c.1101dup | p.Ser368Ilefs*19 | frameshift | 1 | Pathogenic | 0.000000 |
| 32. | c.2490-1G>C | essential splice site | 1 | Pathogenic | 0.000000 | |
| 33. | c.1211dup | p.Val406Serfs*4 | frameshift | 1 | Pathogenic | 0.000000 |
| 34. | c.775G>T | p.E259X | nonsense | 1 | Pathogenic | 0.000000 |
| 35. | c.2119C>T | p.Q707X | nonsense | 1 | Pathogenic | 0.000000 |
| 36. | c.1968del | p.Glu657Serfs*27 | frameshift | 1 | Pathogenic | 0.000000 |
| 37. | c.314del | p.Pro105Leufs*7 | frameshift | 1 | Pathogenic | 0.000000 |
| 38. | c.253_256delGAGT | frameshift | 1 | Pathogenic | 0.000000 | |
| 39. | c.1372_1375del | p.Ile458Glnfs*7 | frameshift | 1 | Pathogenic | 0.000000 |
1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.