PRKAG2 variants in HCM cohorts


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.


Variant Type:      All protein-altering variants     -     Truncating variants     -     Non-Truncating variants
Source:      Combined (OMGL + LMM)     -     OMGL     -     LMM



No. Variant (CDS) Variant (Protein) Variant Type Cases (3973)OMGL classLMM class ExAC frequency
1. c.1592G>A p.R531Qmissense 5Pathogenic (1)Pathogenic (4)0.000000
2. c.905G>A p.R302Qmissense 5Pathogenic (2)Pathogenic (3)0.000000
3. c.431C>T p.P144Lmissense 2VUS (2)0.000024
4. c.1267C>A p.Q423Kmissense 2VUS (1)VUS (1)0.000032
5. c.428C>T p.S143Lmissense 1VUS (1)0.000008
6. c.1648A>C p.I550Lmissense 1VUS (1)0.000032
7. c.47G>C p.S16Tmissense 1VUS (1)0.000000
8. c.1030C>T p.H344Ymissense 1Likely Pathogenic (1)0.000000
9. c.1459T>G p.Y487Dmissense 1VUS (1)0.000000
10. c.563A>G p.E188Gmissense 1VUS (1)0.000000
11. c.1516G>C p.E506Qmissense 1Likely Pathogenic (1)0.000000
12. c.1508A>G p.Q503Rmissense 1VUS (1)0.000016
13. c.1647C>G p.D549Emissense 1VUS (1)0.000000
14. c.1006G>A p.V336Imissense 1VUS (1)0.000000
15. c.989A>G p.Y330Cmissense 1VUS (1)0.000000
16. c.186G>T p.K62Nmissense 1VUS (1)0.000000
17. c.593_594insC p.Asp199fsframeshift 1VUS (1)0.000000
18. c.1315A>G p.I439Vmissense 1VUS (1)0.000024
19. c.1436T>C p.I479Tmissense 1VUS (1)0.000000
20. c.1475T>A p.I492Nmissense 1VUS (1)0.000032
21. c.1592G>T p.R531Lmissense 1VUS favour pathogenic (1)0.000000
22. c.488C>T p.P163Lmissense 1VUS (1)0.000000
23. c.166G>A p.G56Rmissense 1VUS (1)0.000052
24. c.865G>A p.V289Imissense 1VUS (1)0.000008
25. c.1518A>C p.E506Dmissense 1VUS (1)0.000000
26. c.1703C>T p.T568Mmissense 1VUS (1)0.000098
27. c.608G>A p.R203Kmissense 1VUS (1)0.000000
28. c.425C>T p.T142Imissense 1VUS (1)0.000074
29. c.722G>A p.G241Dmissense 1VUS (1)0.000000
30. c.1687C>T p.Q563Xnonsense 1VUS (1)0.000008
31. c.532G>A p.E178Kmissense 1VUS (1)0.000000
32. c.1066G>A p.E356Kmissense 1VUS (1)0.000000

References

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.