TTN truncating variants in DCM cohorts


The table below lists the 22 rare (MAF<0.0001 in ExAC) truncating TTN variants identified in a cohort of 156 DCM patients. When this rare variant frequency of 0.14103 is compared with a background population rate of 0.00876, there is a statistically significant case excess of 0.13227 (p<0.0001), which suggests that approximately 21 of these variants may be pathogenic.


Source:      Combined (OMGL + LMM)     -     OMGL     -     LMM



No. Variant (CDS) Variant (Protein) Variant Type Cases (156)LMM class ExAC frequency
1. c.57995delA p.His19332ProfsX18frameshift 3Likely Pathogenic0.000000
2. c.46782C>A p.Tyr15594Xnonsense 1Likely Pathogenic0.000000
3. c.73845delA p.Glu24615AspfsX9frameshift 1Likely Pathogenic0.000000
4. c.11657delA p.Asp3886ValfsX22frameshift 1VUS favour pathogenic0.000000
5. c.46773T>A p.Tyr15591Xnonsense 1Likely Pathogenic0.000000
6. c.102949C>T p.Gln34317Xnonsense 1Likely Pathogenic0.000000
7. c.90587delA p.Lys30196ArgfsX94frameshift 1Likely Pathogenic0.000000
8. c.86821+2T>A essential splice site 1Likely Pathogenic0.000008
9. c.45307C>T p.Arg15103Xnonsense 1Likely Pathogenic0.000000
10. c.57215delG p.Gly19072GlufsX12frameshift 1Likely Pathogenic0.000000
11. c.77421_77422insC p.Ser25808GlnfsX19frameshift 1Likely Pathogenic0.000000
12. c.41610delA p.Val13871SerfsX7frameshift 1Likely Pathogenic0.000000
13. c.69458_69461dupAGAA p.Asn23154LysfsX14frameshift 1Likely Pathogenic0.000000
14. c.3034C>T p.Arg1012Xnonsense 1Likely Pathogenic0.000000
15. c.46069_46070delAT p.Met15357ValfsX4frameshift 1Likely Pathogenic0.000000
16. c.93897delT p.Phe31299LeufsX14frameshift 1Likely Pathogenic0.000000
17. c.57847+1G>A essential splice site 1Likely Pathogenic0.000000
18. c.89197_89197+2delGGT essential splice site 1Likely Pathogenic0.000000
19. c.12587C>A p.S4196Xnonsense 1VUS favour pathogenic0.000016
20. c.44364delC p.Tyr14789ThrfsX15frameshift 1Likely Pathogenic0.000000

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.