LMNA variants in DCM cohorts


The table below lists the 46 rare (MAF<0.0001 in ExAC) protein-altering LMNA variants identified in a cohort of 1044 DCM patients (304 patients from OMGL, 740 patients from LMM). When this rare variant frequency of 0.04406 is compared with a background population rate of 0.00622, there is a statistically significant case excess of 0.03784 (p<0.0001), which suggests that approximately 40 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 (1044)OMGL classLMM class ExAC frequency
1. c.961C>T p.R321Xnonsense 3Pathogenic (2)Likely Pathogenic (1)0.000000
2. c.1003C>T p.R335Wmissense 3Likely Pathogenic (3)0.000000
3. c.673C>T p.R225Xnonsense 2Pathogenic (2)0.000000
4. c.1621C>T p.R541Cmissense 2Likely Pathogenic (2)0.000000
5. c.868G>A p.E290Kmissense 2VUS (1)VUS favour pathogenic (1)0.000000
6. c.481G>A p.E161Kmissense 2Pathogenic (2)0.000000
7. c.154C>G p.L52Vmissense 1Likely Pathogenic (1)0.000000
8. c.863C>G p.A288Gmissense 1Likely Pathogenic (1)0.000000
9. c.356+2T>G essential splice site 1Pathogenic (1)0.000000
10. c.266G>A p.R89Hmissense 1VUS (1)0.000000
11. c.1304_1307del p.Arg435Leufs*44frameshift 1Pathogenic (1)0.000000
12. c.1622G>A p.R541Hmissense 1Likely Pathogenic (1)0.000093
13. c.513+1G>C essential splice site 1Likely Pathogenic (1)0.000000
14. c.1442A>G p.Y481Cmissense 1Likely Pathogenic (1)0.000000
15. c.436G>A p.A146Tmissense 1VUS favour pathogenic (1)0.000000
16. c.949G>A p.E317Kmissense 1Likely Pathogenic (1)0.000000
17. c.1111_1125del p.Met371_Ala375delinframe 1Likely Pathogenic (1)0.000000
18. c.970del p.Glu324Argfs*156frameshift 1Pathogenic (1)0.000000
19. c.1106T>C p.L369Pmissense 1Likely Pathogenic (1)0.000000
20. c.16C>T p.Q6Xnonsense 1Pathogenic (1)0.000000
21. c.700C>T p.Q234Xnonsense 1Likely Pathogenic (1)0.000000
22. c.640-2A>G essential splice site 1Pathogenic (1)0.000000
23. c.350A>G p.K117Rmissense 1VUS (1)0.000068
24. c.992G>A p.R331Qmissense 1Likely Pathogenic (1)0.000016
25. c.1526dupC p.Thr510Tyrfs*42frameshift 1Likely Pathogenic (1)0.000000
26. c.763delC frameshift 1Likely Pathogenic (1)0.000000
27. c.448A>C p.T150Pmissense 1Likely Pathogenic (1)0.000000
28. c.958delC frameshift 1Likely Pathogenic (1)0.000000
29. c.175C>A p.L59Mmissense 1VUS (1)0.000000
30. c.1412G>A p.R471Hmissense 1Likely Pathogenic (1)0.000000
31. c.739G>A p.E247Kmissense 1VUS (1)0.000000
32. c.1046G>A p.R349Qmissense 1VUS (1)0.000000
33. c.1129C>T p.R377Cmissense 1Likely Pathogenic (1)0.000000
34. c.799T>C p.Y267Hmissense 1Pathogenic (1)0.000000
35. c.976T>A p.S326Tmissense 1Likely Pathogenic (1)0.000059
36. c.356G>C p.R119Pmissense 1Likely Pathogenic (1)0.000000
37. c.1201C>T p.R401Cmissense 1VUS (1)0.000033
38. c.811-2A>C essential splice site 1Pathogenic (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. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.