The table below lists the 101 rare (MAF<0.0001 in ExAC) protein-altering PKP2 variants identified in a cohort of 361 ARVC patients. When this rare variant frequency of 0.27978 is compared with a background population rate of 0.01358, there is a statistically significant case excess of 0.26620 (p<0.0001), which suggests that approximately 96 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.275T>A | p.L92X | nonsense | 3 | Pathogenic | 0.000000 |
| 5. | c.1132C>T | p.Q378X | nonsense | 3 | Pathogenic | 0.000000 |
| 6. | c.1237C>T | p.R413X | nonsense | 2 | Pathogenic | 0.000016 |
| 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.337-2A>T | essential splice site | 2 | Pathogenic | 0.000000 | |
| 10. | c.1901del | p.Asn634Thrfs*22 | frameshift | 2 | Pathogenic | 0.000000 |
| 11. | c.148_151delACAG | p.Thr50SerfsX61 | frameshift | 2 | Pathogenic | 0.000000 |
| 12. | c.358G>T | p.E120X | nonsense | 2 | Pathogenic | 0.000000 |
| 13. | c.2490-1G>C | essential splice site | 1 | Pathogenic | 0.000000 | |
| 14. | c.1171_1378del | p.Val391Thrfs*6 | frameshift | 1 | Likely Pathogenic | 0.000000 |
| 15. | c.1063C>T | p.R355X | nonsense | 1 | Pathogenic | 0.000008 |
| 16. | c.2062T>C | p.S688P | missense | 1 | VUS | 0.000032 |
| 17. | c.1101dup | p.Ser368Ilefs*19 | frameshift | 1 | Pathogenic | 0.000000 |
| 18. | c.2540T>C | p.L847P | missense | 1 | VUS | 0.000000 |
| 19. | c.68G>A | p.G23E | missense | 1 | VUS | 0.000000 |
| 20. | c.1211dup | p.Val406Serfs*4 | frameshift | 1 | Pathogenic | 0.000000 |
| 21. | c.314del | p.Pro105Leufs*7 | frameshift | 1 | Pathogenic | 0.000000 |
| 22. | c.663C>A | p.Y221X | nonsense | 1 | Pathogenic | 0.000008 |
| 23. | c.1177C>T | p.Q393X | nonsense | 1 | Pathogenic | 0.000000 |
| 24. | c.253_256delGAGT | frameshift | 1 | Pathogenic | 0.000000 | |
| 25. | c.1372_1375del | p.Ile458Glnfs*7 | frameshift | 1 | Pathogenic | 0.000000 |
| 26. | c.941G>A | p.G314E | missense | 1 | VUS | 0.000057 |
| 27. | c.1968del | p.Glu657Serfs*27 | frameshift | 1 | Pathogenic | 0.000000 |
| 28. | c.1754C>G | p.S585X | nonsense | 1 | Pathogenic | 0.000000 |
| 29. | c.968_975delinsGCCTTT | p.Gln323Argfs*12 | frameshift | 1 | Pathogenic | 0.000000 |
| 30. | c.2509delA | p.Ser837ValfsX94 | frameshift | 1 | Pathogenic | 0.000000 |
| 31. | c.1689-1G>C | essential splice site | 1 | Pathogenic | 0.000008 | |
| 32. | c.1114G>A | p.A372T | missense | 1 | VUS | 0.000008 |
| 33. | c.2058T>A | p.Y686X | nonsense | 1 | Pathogenic | 0.000000 |
| 34. | c.2119C>T | p.Q707X | nonsense | 1 | Pathogenic | 0.000000 |
| 35. | c.1125_1132del | p.Phe376Alafs*8 | frameshift | 1 | Pathogenic | 0.000000 |
| 36. | c.1892delinsTCC | p.Tyr631Phefs*26 | frameshift | 1 | Pathogenic | 0.000000 |
| 37. | c.2493T>A | p.Y831X | nonsense | 1 | Pathogenic | 0.000000 |
| 38. | c.2393C>G | p.T798R | missense | 1 | VUS | 0.000000 |
| 39. | c.1170+1G>C | essential splice site | 1 | Pathogenic | 0.000000 | |
| 40. | c.1917_1935dup | p.Gly646* | frameshift | 1 | Pathogenic | 0.000000 |
| 41. | c.215del | p.Val72Glyfs*40 | frameshift | 1 | Pathogenic | 0.000000 |
| 42. | c.235C>T | p.R79X | nonsense | 1 | Pathogenic | 0.000000 |
| 43. | c.1255_1279dup | p.Asn427Ilefs*7 | frameshift | 1 | Likely Pathogenic | 0.000000 |
| 44. | c.775G>T | p.E259X | nonsense | 1 | Pathogenic | 0.000000 |
| 45. | c.356dup | p.Tyr119* | 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.