TTN truncating variants in DCM cohorts

The table below lists the 67 rare (MAF<0.0001 in ExAC) truncating TTN variants identified in a cohort of 460 DCM patients (304 patients from OMGL, 156 patients from LMM). When this rare variant frequency of 0.14565 is compared with a background population rate of 0.00876, there is a statistically significant case excess of 0.13689 (p<0.0001), which suggests that approximately 63 of these variants may be pathogenic.

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

No.	Variant (CDS)▼	Variant (Protein)	Variant Type▼	Cases (460)▼	OMGL class	LMM class	ExAC frequency
1.	c.57995delA	p.His19332ProfsX18	frameshift	3		Likely Pathogenic (3)	0.000000
2.	c.97417del	p.Arg32473Valfs*19	frameshift	2	VUS (2)		0.000000
3.	c.16077del	p.Phe5359Leufs*28	frameshift	1	VUS (1)		0.000000
4.	c.57215delG	p.Gly19072GlufsX12	frameshift	1		Likely Pathogenic (1)	0.000000
5.	c.51436C>T	p.Q17146X	nonsense	1	VUS (1)		0.000000
6.	c.11657delA	p.Asp3886ValfsX22	frameshift	1		VUS favour pathogenic (1)	0.000000
7.	c.63625C>T	p.R21209X	nonsense	1	VUS (1)		0.000000
8.	c.46773T>A	p.Tyr15591X	nonsense	1		Likely Pathogenic (1)	0.000000
9.	c.77421_77422insC	p.Ser25808GlnfsX19	frameshift	1		Likely Pathogenic (1)	0.000000
10.	c.98506C>T	p.R32836X	nonsense	1	VUS (1)		0.000000
11.	c.76865G>A	p.W25622X	nonsense	1	VUS (1)		0.000000
12.	c.92652_92659del	p.Asp30885Serfs*3	frameshift	1	VUS (1)		0.000000
13.	c.44272C>T	p.R14758X	nonsense	1	VUS (1)		0.000008
14.	c.60163_60164del	p.Ile20055Cysfs*7	frameshift	1	VUS (1)		0.000000
15.	c.86821+2T>A		essential splice site	1		Likely Pathogenic (1)	0.000008
16.	c.70200_70203dup	p.Ile23402Aspfs*6	frameshift	1	VUS (1)		0.000000
17.	c.31035T>G	p.Y10345X	nonsense	1	VUS (1)		0.000000
18.	c.85238del	p.Thr28413Ilefs*3	frameshift	1	VUS (1)		0.000000
19.	c.69458_69461dupAGAA	p.Asn23154LysfsX14	frameshift	1		Likely Pathogenic (1)	0.000000
20.	c.45307C>T	p.Arg15103X	nonsense	1		Likely Pathogenic (1)	0.000000
21.	c.12742C>T	p.Q4248X	nonsense	1	VUS (1)		0.000000
22.	c.93897delT	p.Phe31299LeufsX14	frameshift	1		Likely Pathogenic (1)	0.000000
23.	c.98265_98268dup	p.His32757Asnfs*4	frameshift	1	VUS (1)		0.000000
24.	c.61495C>T	p.R20499X	nonsense	1	VUS (1)		0.000000
25.	c.74104C>T	p.Q24702X	nonsense	1	VUS (1)		0.000000
26.	c.46803G>A	p.W15601X	nonsense	1	VUS (1)		0.000000
27.	c.85946del	p.Val28649Glyfs*20	frameshift	1	VUS (1)		0.000000
28.	c.99058del	p.Glu33020Argfs*41	frameshift	1	VUS (1)		0.000000
29.	c.60940del	p.Thr20314Leufs*5	frameshift	1	VUS (1)		0.000000
30.	c.41610delA	p.Val13871SerfsX7	frameshift	1		Likely Pathogenic (1)	0.000000
31.	c.14194C>T	p.Q4732X	nonsense	1	VUS (1)		0.000000
32.	c.57847+1G>A		essential splice site	1		Likely Pathogenic (1)	0.000000
33.	c.47314C>T	p.R15772X	nonsense	1	VUS (1)		0.000000
34.	c.46782C>A	p.Tyr15594X	nonsense	1		Likely Pathogenic (1)	0.000000
35.	c.89197_89197+2delGGT		essential splice site	1		Likely Pathogenic (1)	0.000000
36.	c.88727delC	p.Thr29576LysfsTer36	frameshift	1	VUS (1)		0.000008
37.	c.12358C>T	p.Q4120X	nonsense	1	VUS (1)		0.000008
38.	c.63025C>T	p.R21009X	nonsense	1	VUS (1)		0.000000
39.	c.76822del	p.Leu25608*	frameshift	1	VUS (1)		0.000000
40.	c.89787del	p.Val29930Cysfs*36	frameshift	1	VUS (1)		0.000000
41.	c.24019C>T	p.R8007X	nonsense	1	VUS (1)		0.000000
42.	c.51444del	p.Asp17149Ilefs*4	frameshift	1	VUS (1)		0.000000
43.	c.3034C>T	p.Arg1012X	nonsense	1		Likely Pathogenic (1)	0.000000
44.	c.67952_67955dup	p.Lys22652Asnfs*4	frameshift	1	VUS (1)		0.000000
45.	c.12587C>A	p.S4196X	nonsense	1		VUS favour pathogenic (1)	0.000016
46.	c.73845delA	p.Glu24615AspfsX9	frameshift	1		Likely Pathogenic (1)	0.000000
47.	c.46069_46070delAT	p.Met15357ValfsX4	frameshift	1		Likely Pathogenic (1)	0.000000
48.	c.82470G>A	p.W27490X	nonsense	1	VUS (1)		0.000000
49.	c.56572C>T	p.R18858X	nonsense	1	VUS (1)		0.000027
50.	c.70563dup	p.Glu23522Argfs*10	frameshift	1	VUS (1)		0.000000
51.	c.35083G>T	p.E11695X	nonsense	1	VUS (1)		0.000000
52.	c.85713G>A	p.W28571X	nonsense	1	VUS (1)		0.000000
53.	c.60643_60644del	p.Arg20215Glufs*13	frameshift	1	VUS (1)		0.000000
54.	c.46925_46928del	p.Lys15642Metfs*10	frameshift	1	VUS (1)		0.000000
55.	c.44364delC	p.Tyr14789ThrfsX15	frameshift	1		Likely Pathogenic (1)	0.000000
56.	c.102949C>T	p.Gln34317X	nonsense	1		Likely Pathogenic (1)	0.000000
57.	c.13900G>T	p.E4634X	nonsense	1	VUS (1)		0.000000
58.	c.90587delA	p.Lys30196ArgfsX94	frameshift	1		Likely Pathogenic (1)	0.000000
59.	c.98504_98505del	p.Arg32835Thrfs*5	frameshift	1	VUS (1)		0.000000
60.	c.64453C>T	p.R21485X	nonsense	1	VUS (1)		0.000025
61.	c.86229delinsAA	p.Ile28744Asnfs*12	frameshift	1	VUS (1)		0.000000
62.	c.100825C>T	p.R33609X	nonsense	1	VUS (1)		0.000000
63.	c.62722C>T	p.R20908X	nonsense	1	VUS (1)		0.000000
64.	c.75633_75636dup	p.Val25213Cysfs*25	frameshift	1	VUS (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.