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.989A>G p.Y330Cmissense 1VUS (1)0.000000
6. c.1592G>T p.R531Lmissense 1VUS favour pathogenic (1)0.000000
7. c.1475T>A p.I492Nmissense 1VUS (1)0.000032
8. c.1508A>G p.Q503Rmissense 1VUS (1)0.000016
9. c.865G>A p.V289Imissense 1VUS (1)0.000008
10. c.1436T>C p.I479Tmissense 1VUS (1)0.000000
11. c.186G>T p.K62Nmissense 1VUS (1)0.000000
12. c.1703C>T p.T568Mmissense 1VUS (1)0.000098
13. c.1518A>C p.E506Dmissense 1VUS (1)0.000000
14. c.1687C>T p.Q563Xnonsense 1VUS (1)0.000008
15. c.488C>T p.P163Lmissense 1VUS (1)0.000000
16. c.722G>A p.G241Dmissense 1VUS (1)0.000000
17. c.428C>T p.S143Lmissense 1VUS (1)0.000008
18. c.608G>A p.R203Kmissense 1VUS (1)0.000000
19. c.532G>A p.E178Kmissense 1VUS (1)0.000000
20. c.166G>A p.G56Rmissense 1VUS (1)0.000052
21. c.1066G>A p.E356Kmissense 1VUS (1)0.000000
22. c.1030C>T p.H344Ymissense 1Likely Pathogenic (1)0.000000
23. c.1648A>C p.I550Lmissense 1VUS (1)0.000032
24. c.425C>T p.T142Imissense 1VUS (1)0.000074
25. c.1459T>G p.Y487Dmissense 1VUS (1)0.000000
26. c.47G>C p.S16Tmissense 1VUS (1)0.000000
27. c.1006G>A p.V336Imissense 1VUS (1)0.000000
28. c.1647C>G p.D549Emissense 1VUS (1)0.000000
29. c.1315A>G p.I439Vmissense 1VUS (1)0.000024
30. c.593_594insC p.Asp199fsframeshift 1VUS (1)0.000000
31. c.1516G>C p.E506Qmissense 1Likely Pathogenic (1)0.000000
32. c.563A>G p.E188Gmissense 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.