TNNT2 variants in DCM cohorts


The table below lists the 36 rare (MAF<0.0001 in ExAC) protein-altering TNNT2 variants identified in a cohort of 1254 DCM patients (498 patients from OMGL, 756 patients from LMM). When this rare variant frequency of 0.02871 is compared with a background population rate of 0.00242, there is a statistically significant case excess of 0.02629 (p<0.0001), which suggests that approximately 33 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 (1254)OMGL classLMM class ExAC frequency
1. c.629_631delAGA inframe 18Pathogenic (7)Pathogenic (11)0.000000
2. c.421C>T p.R141Wmissense 6Pathogenic (1)Pathogenic (5)0.000000
3. c.391C>T p.R131Wmissense 2Likely Pathogenic (1)VUS favour pathogenic (1)0.000008
4. c.415C>T p.R139Cmissense 1VUS (1)0.000000
5. c.325C>T p.H109Ymissense 1VUS favour pathogenic (1)0.000000
6. c.476G>A p.R159Qmissense 1VUS (1)0.000000
7. c.530C>A p.A177Dmissense 1VUS (1)0.000000
8. c.400C>G p.R134Gmissense 1Likely Pathogenic (1)0.000000
9. c.734C>T p.A245Vmissense 1VUS (1)0.000008
10. c.392G>A p.R131Qmissense 1Likely Pathogenic (1)0.000000
11. c.178A>G p.M60Vmissense 1VUS (1)0.000049
12. c.613C>T p.R205Wmissense 1Likely Pathogenic (1)0.000000
13. c.416G>A p.R139Hmissense 1Likely Pathogenic (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.