The table below lists the 42 rare (MAF<0.0001 in ExAC) protein-altering PRKAG2 variants identified in a cohort of 3973 HCM patients (1535 patients from OMGL, 2438 patients from LMM). When this rare variant frequency of 0.01057 is compared with a background population rate of 0.00532, there is a statistically significant case excess of 0.00525 (p=0.0001), which suggests that approximately 21 of these variants may be pathogenic.
| No. | Variant (CDS)▼ | Variant (Protein) | Variant Type▼ | Cases (3973)▼ | OMGL class | LMM class | ExAC frequency |
|---|---|---|---|---|---|---|---|
| 1. | c.1516G>C | p.E506Q | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 2. | c.865G>A | p.V289I | missense | 1 | VUS (1) | 0.000008 | |
| 3. | c.1518A>C | p.E506D | missense | 1 | VUS (1) | 0.000000 | |
| 4. | c.1508A>G | p.Q503R | missense | 1 | VUS (1) | 0.000016 | |
| 5. | c.1703C>T | p.T568M | missense | 1 | VUS (1) | 0.000098 | |
| 6. | c.608G>A | p.R203K | missense | 1 | VUS (1) | 0.000000 | |
| 7. | c.1592G>A | p.R531Q | missense | 5 | Pathogenic (1) | Pathogenic (4) | 0.000000 |
| 8. | c.722G>A | p.G241D | missense | 1 | VUS (1) | 0.000000 | |
| 9. | c.186G>T | p.K62N | missense | 1 | VUS (1) | 0.000000 | |
| 10. | c.1066G>A | p.E356K | missense | 1 | VUS (1) | 0.000000 | |
| 11. | c.532G>A | p.E178K | missense | 1 | VUS (1) | 0.000000 | |
| 12. | c.428C>T | p.S143L | missense | 1 | VUS (1) | 0.000008 | |
| 13. | c.1267C>A | p.Q423K | missense | 2 | VUS (1) | VUS (1) | 0.000032 |
| 14. | c.47G>C | p.S16T | missense | 1 | VUS (1) | 0.000000 | |
| 15. | c.1030C>T | p.H344Y | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 16. | c.1459T>G | p.Y487D | missense | 1 | VUS (1) | 0.000000 | |
| 17. | c.166G>A | p.G56R | missense | 1 | VUS (1) | 0.000052 | |
| 18. | c.1648A>C | p.I550L | missense | 1 | VUS (1) | 0.000032 | |
| 19. | c.563A>G | p.E188G | missense | 1 | VUS (1) | 0.000000 | |
| 20. | c.905G>A | p.R302Q | missense | 5 | Pathogenic (2) | Pathogenic (3) | 0.000000 |
| 21. | c.1647C>G | p.D549E | missense | 1 | VUS (1) | 0.000000 | |
| 22. | c.425C>T | p.T142I | missense | 1 | VUS (1) | 0.000074 | |
| 23. | c.1006G>A | p.V336I | missense | 1 | VUS (1) | 0.000000 | |
| 24. | c.989A>G | p.Y330C | missense | 1 | VUS (1) | 0.000000 | |
| 25. | c.431C>T | p.P144L | missense | 2 | VUS (2) | 0.000024 | |
| 26. | c.1315A>G | p.I439V | missense | 1 | VUS (1) | 0.000024 | |
| 27. | c.1475T>A | p.I492N | missense | 1 | VUS (1) | 0.000032 | |
| 28. | c.1592G>T | p.R531L | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 29. | c.1436T>C | p.I479T | missense | 1 | VUS (1) | 0.000000 | |
| 30. | c.488C>T | p.P163L | missense | 1 | VUS (1) | 0.000000 | |
| 31. | c.1687C>T | p.Q563X | nonsense | 1 | VUS (1) | 0.000008 | |
| 32. | c.593_594insC | p.Asp199fs | frameshift | 1 | VUS (1) | 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.
2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.