PRKAG2 non-truncating variants in HCM cohorts


The table below lists the 40 rare (MAF<0.0001 in ExAC) non-truncating PRKAG2 variants identified in a cohort of 3973 HCM patients (1535 patients from OMGL, 2438 patients from LMM). When this rare variant frequency of 0.01007 is compared with a background population rate of 0.00520, there is a statistically significant case excess of 0.00487 (p=0.0002), which suggests that approximately 19 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.905G>A p.R302Qmissense 5Pathogenic (2)Pathogenic (3)0.000000
2. c.1592G>A p.R531Qmissense 5Pathogenic (1)Pathogenic (4)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.865G>A p.V289Imissense 1VUS (1)0.000008
6. c.1459T>G p.Y487Dmissense 1VUS (1)0.000000
7. c.425C>T p.T142Imissense 1VUS (1)0.000074
8. c.1648A>C p.I550Lmissense 1VUS (1)0.000032
9. c.563A>G p.E188Gmissense 1VUS (1)0.000000
10. c.1647C>G p.D549Emissense 1VUS (1)0.000000
11. c.1006G>A p.V336Imissense 1VUS (1)0.000000
12. c.1315A>G p.I439Vmissense 1VUS (1)0.000024
13. c.989A>G p.Y330Cmissense 1VUS (1)0.000000
14. c.532G>A p.E178Kmissense 1VUS (1)0.000000
15. c.1516G>C p.E506Qmissense 1Likely Pathogenic (1)0.000000
16. c.1030C>T p.H344Ymissense 1Likely Pathogenic (1)0.000000
17. c.1436T>C p.I479Tmissense 1VUS (1)0.000000
18. c.1508A>G p.Q503Rmissense 1VUS (1)0.000016
19. c.1475T>A p.I492Nmissense 1VUS (1)0.000032
20. c.1518A>C p.E506Dmissense 1VUS (1)0.000000
21. c.488C>T p.P163Lmissense 1VUS (1)0.000000
22. c.186G>T p.K62Nmissense 1VUS (1)0.000000
23. c.1703C>T p.T568Mmissense 1VUS (1)0.000098
24. c.722G>A p.G241Dmissense 1VUS (1)0.000000
25. c.608G>A p.R203Kmissense 1VUS (1)0.000000
26. c.428C>T p.S143Lmissense 1VUS (1)0.000008
27. c.1592G>T p.R531Lmissense 1VUS favour pathogenic (1)0.000000
28. c.1066G>A p.E356Kmissense 1VUS (1)0.000000
29. c.166G>A p.G56Rmissense 1VUS (1)0.000052
30. c.47G>C p.S16Tmissense 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.