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.1621C>T p.R541Cmissense 2Likely Pathogenic (2)0.000000
4. c.868G>A p.E290Kmissense 2VUS (1)VUS favour pathogenic (1)0.000000
5. c.481G>A p.E161Kmissense 2Pathogenic (2)0.000000
6. c.673C>T p.R225Xnonsense 2Pathogenic (2)0.000000
7. c.513+1G>C essential splice site 1Likely Pathogenic (1)0.000000
8. c.1046G>A p.R349Qmissense 1VUS (1)0.000000
9. c.1201C>T p.R401Cmissense 1VUS (1)0.000033
10. c.1106T>C p.L369Pmissense 1Likely Pathogenic (1)0.000000
11. c.811-2A>C essential splice site 1Pathogenic (1)0.000000
12. c.436G>A p.A146Tmissense 1VUS favour pathogenic (1)0.000000
13. c.266G>A p.R89Hmissense 1VUS (1)0.000000
14. c.16C>T p.Q6Xnonsense 1Pathogenic (1)0.000000
15. c.356+2T>G essential splice site 1Pathogenic (1)0.000000
16. c.949G>A p.E317Kmissense 1Likely Pathogenic (1)0.000000
17. c.1622G>A p.R541Hmissense 1Likely Pathogenic (1)0.000093
18. c.700C>T p.Q234Xnonsense 1Likely Pathogenic (1)0.000000
19. c.1526dupC p.Thr510Tyrfs*42frameshift 1Likely Pathogenic (1)0.000000
20. c.763delC frameshift 1Likely Pathogenic (1)0.000000
21. c.1304_1307del p.Arg435Leufs*44frameshift 1Pathogenic (1)0.000000
22. c.1129C>T p.R377Cmissense 1Likely Pathogenic (1)0.000000
23. c.1111_1125del p.Met371_Ala375delinframe 1Likely Pathogenic (1)0.000000
24. c.970del p.Glu324Argfs*156frameshift 1Pathogenic (1)0.000000
25. c.992G>A p.R331Qmissense 1Likely Pathogenic (1)0.000016
26. c.448A>C p.T150Pmissense 1Likely Pathogenic (1)0.000000
27. c.350A>G p.K117Rmissense 1VUS (1)0.000068
28. c.1412G>A p.R471Hmissense 1Likely Pathogenic (1)0.000000
29. c.958delC frameshift 1Likely Pathogenic (1)0.000000
30. c.356G>C p.R119Pmissense 1Likely Pathogenic (1)0.000000
31. c.640-2A>G essential splice site 1Pathogenic (1)0.000000
32. c.976T>A p.S326Tmissense 1Likely Pathogenic (1)0.000059
33. c.175C>A p.L59Mmissense 1VUS (1)0.000000
34. c.799T>C p.Y267Hmissense 1Pathogenic (1)0.000000
35. c.154C>G p.L52Vmissense 1Likely Pathogenic (1)0.000000
36. c.863C>G p.A288Gmissense 1Likely Pathogenic (1)0.000000
37. c.1442A>G p.Y481Cmissense 1Likely Pathogenic (1)0.000000
38. c.739G>A p.E247Kmissense 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. 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.