TNNT2 variants in HCM cohorts

The table below lists the 119 rare (MAF<0.0001 in ExAC) protein-altering TNNT2 variants identified in a cohort of 6103 HCM patients (3191 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.01950 is compared with a background population rate of 0.00242, there is a statistically significant case excess of 0.01708 (p<0.0001), which suggests that approximately 105 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 (6103)▼	OMGL class	LMM class	ExAC frequency
1.	c.807C>A	p.N269K	missense	1		Likely Pathogenic (1)	0.000000
2.	c.773A>T	p.K258I	missense	2		VUS favour pathogenic (2)	0.000000
3.	c.249G>C	p.E83D	missense	1		VUS (1)	0.000000
4.	c.244G>A	p.G82R	missense	1		Likely Pathogenic (1)	0.000000
5.	c.426T>G	p.N142K	missense	1	VUS (1)		0.000000
6.	c.392G>A	p.R131Q	missense	1	VUS (1)		0.000000
7.	c.236T>A	p.I79N	missense	10	Pathogenic (8)	Pathogenic (2)	0.000000
8.	c.274C>T	p.R92W	missense	8	Pathogenic (5)	Pathogenic (3)	0.000008
9.	c.785A>G	p.N262S	missense	5	VUS (4)	VUS (1)	0.000000
10.	c.330T>G	p.F110L	missense	1		Likely Pathogenic (1)	0.000000
11.	c.652G>T	p.V218L	missense	1		VUS favour benign (1)	0.000032
12.	c.451C>T	p.R151C	missense	1	VUS (1)		0.000000
13.	c.857G>A	p.R286H	missense	3		VUS favour pathogenic (3)	0.000078
14.	c.281G>T	p.R94L	missense	4	Likely Pathogenic (3)	Pathogenic (1)	0.000000
15.	c.238C>T	p.P80S	missense	1		VUS favour pathogenic (1)	0.000000
16.	c.257A>C	p.D86A	missense	2		Likely Pathogenic (2)	0.000008
17.	c.487G>A	p.E163K	missense	1	Likely Pathogenic (1)		0.000000
18.	c.281G>A	p.R94H	missense	4		Likely Pathogenic (4)	0.000000
19.	c.649A>G	p.K217E	missense	1		VUS (1)	0.000000
20.	c.145G>C	p.E49Q	missense	1	VUS (1)		0.000008
21.	c.283A>G	p.M95V	missense	1		VUS (1)	0.000016
22.	c.291G>T	p.K97N	missense	1	Likely Pathogenic (1)		0.000000
23.	c.269T>A	p.I90N	missense	1	VUS (1)		0.000000
24.	c.311C>T	p.A104V	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000008
25.	c.856C>T	p.R286C	missense	6	Likely Pathogenic (4)	VUS favour pathogenic (2)	0.000011
26.	c.106G>C	p.A36P	missense	1		VUS (1)	0.000049
27.	c.388C>T	p.R130C	missense	4	Likely Pathogenic (2)	Likely Pathogenic (2)	0.000000
28.	c.251G>C	p.R84T	missense	2		VUS favour pathogenic (2)	0.000000
29.	c.805A>G	p.N269D	missense	1	VUS (1)		0.000017
30.	c.502G>C	p.A168P	missense	1	VUS (1)		0.000000
31.	c.400C>T	p.R134W	missense	1	VUS (1)		0.000000
32.	c.536C>T	p.S179F	missense	2		Likely Pathogenic (2)	0.000000
33.	c.833G>C	p.R278P	missense	6	Likely Pathogenic (5)	VUS favour pathogenic (1)	0.000000
34.	c.833G>A	p.R278H	missense	2	VUS (1)	VUS (1)	0.000021
35.	c.247G>A	p.E83K	missense	1		VUS (1)	0.000000
36.	c.252A>T	p.R84S	missense	2		VUS (2)	0.000000
37.	c.767A>G	p.Q256R	missense	1	VUS (1)		0.000000
38.	c.534G>C	p.L178F	missense	1		VUS (1)	0.000000
39.	c.256G>T	p.D86Y	missense	1	VUS (1)		0.000000
40.	c.421C>T	p.R141W	missense	1		Pathogenic (1)	0.000000
41.	c.275G>A	p.R92Q	missense	4	Pathogenic (1)	Pathogenic (3)	0.000000
42.	c.860G>A	p.W287X	nonsense	4		Pathogenic (4)	0.000011
43.	c.571-1G>A		essential splice site	4	VUS (4)		0.000017
44.	c.821+1G>T		essential splice site	1		Likely Pathogenic (1)	0.000000
45.	c.821+1G>C		essential splice site	1	Pathogenic (1)		0.000000
46.	c.460-1G>C		essential splice site	1	VUS (1)		0.000000
47.	c.487_489delGAG		inframe	14	Pathogenic (5)	Pathogenic (9)	0.000000
48.	c.678_680del	p.Glu226del	inframe	1	VUS (1)		0.000000
49.	c.147_149delAGA	p.Glu51del	inframe	1	VUS (1)		0.000008

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. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.