LMNA truncating variants in DCM cohorts


The table below lists the 16 rare (MAF<0.0001 in ExAC) truncating LMNA variants identified in a cohort of 1044 DCM patients (304 patients from OMGL, 740 patients from LMM). When this rare variant frequency of 0.01533 is compared with a background population rate of 0.00014, there is a statistically significant case excess of 0.01519 (p<0.0001), which suggests that approximately 16 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.673C>T p.R225Xnonsense 2Pathogenic (2)0.000000
3. c.16C>T p.Q6Xnonsense 1Pathogenic (1)0.000000
4. c.958delC frameshift 1Likely Pathogenic (1)0.000000
5. c.970del p.Glu324Argfs*156frameshift 1Pathogenic (1)0.000000
6. c.640-2A>G essential splice site 1Pathogenic (1)0.000000
7. c.513+1G>C essential splice site 1Likely Pathogenic (1)0.000000
8. c.1526dupC p.Thr510Tyrfs*42frameshift 1Likely Pathogenic (1)0.000000
9. c.700C>T p.Q234Xnonsense 1Likely Pathogenic (1)0.000000
10. c.1304_1307del p.Arg435Leufs*44frameshift 1Pathogenic (1)0.000000
11. c.811-2A>C essential splice site 1Pathogenic (1)0.000000
12. c.763delC frameshift 1Likely Pathogenic (1)0.000000
13. c.356+2T>G 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.