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.247G>A	p.E83K	missense	1		VUS (1)	0.000000
2.	c.833G>C	p.R278P	missense	6	Likely Pathogenic (5)	VUS favour pathogenic (1)	0.000000
3.	c.833G>A	p.R278H	missense	2	VUS (1)	VUS (1)	0.000021
4.	c.281G>T	p.R94L	missense	4	Likely Pathogenic (3)	Pathogenic (1)	0.000000
5.	c.767A>G	p.Q256R	missense	1	VUS (1)		0.000000
6.	c.534G>C	p.L178F	missense	1		VUS (1)	0.000000
7.	c.252A>T	p.R84S	missense	2		VUS (2)	0.000000
8.	c.256G>T	p.D86Y	missense	1	VUS (1)		0.000000
9.	c.311C>T	p.A104V	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000008
10.	c.807C>A	p.N269K	missense	1		Likely Pathogenic (1)	0.000000
11.	c.244G>A	p.G82R	missense	1		Likely Pathogenic (1)	0.000000
12.	c.773A>T	p.K258I	missense	2		VUS favour pathogenic (2)	0.000000
13.	c.249G>C	p.E83D	missense	1		VUS (1)	0.000000
14.	c.392G>A	p.R131Q	missense	1	VUS (1)		0.000000
15.	c.426T>G	p.N142K	missense	1	VUS (1)		0.000000
16.	c.536C>T	p.S179F	missense	2		Likely Pathogenic (2)	0.000000
17.	c.785A>G	p.N262S	missense	5	VUS (4)	VUS (1)	0.000000
18.	c.330T>G	p.F110L	missense	1		Likely Pathogenic (1)	0.000000
19.	c.652G>T	p.V218L	missense	1		VUS favour benign (1)	0.000032
20.	c.451C>T	p.R151C	missense	1	VUS (1)		0.000000
21.	c.421C>T	p.R141W	missense	1		Pathogenic (1)	0.000000
22.	c.257A>C	p.D86A	missense	2		Likely Pathogenic (2)	0.000008
23.	c.275G>A	p.R92Q	missense	4	Pathogenic (1)	Pathogenic (3)	0.000000
24.	c.238C>T	p.P80S	missense	1		VUS favour pathogenic (1)	0.000000
25.	c.145G>C	p.E49Q	missense	1	VUS (1)		0.000008
26.	c.283A>G	p.M95V	missense	1		VUS (1)	0.000016
27.	c.487G>A	p.E163K	missense	1	Likely Pathogenic (1)		0.000000
28.	c.281G>A	p.R94H	missense	4		Likely Pathogenic (4)	0.000000
29.	c.649A>G	p.K217E	missense	1		VUS (1)	0.000000
30.	c.269T>A	p.I90N	missense	1	VUS (1)		0.000000
31.	c.291G>T	p.K97N	missense	1	Likely Pathogenic (1)		0.000000
32.	c.236T>A	p.I79N	missense	10	Pathogenic (8)	Pathogenic (2)	0.000000
33.	c.856C>T	p.R286C	missense	6	Likely Pathogenic (4)	VUS favour pathogenic (2)	0.000011
34.	c.251G>C	p.R84T	missense	2		VUS favour pathogenic (2)	0.000000
35.	c.274C>T	p.R92W	missense	8	Pathogenic (5)	Pathogenic (3)	0.000008
36.	c.106G>C	p.A36P	missense	1		VUS (1)	0.000049
37.	c.388C>T	p.R130C	missense	4	Likely Pathogenic (2)	Likely Pathogenic (2)	0.000000
38.	c.400C>T	p.R134W	missense	1	VUS (1)		0.000000
39.	c.805A>G	p.N269D	missense	1	VUS (1)		0.000017
40.	c.502G>C	p.A168P	missense	1	VUS (1)		0.000000
41.	c.857G>A	p.R286H	missense	3		VUS favour pathogenic (3)	0.000078
42.	c.860G>A	p.W287X	nonsense	4		Pathogenic (4)	0.000011
43.	c.460-1G>C		essential splice site	1	VUS (1)		0.000000
44.	c.571-1G>A		essential splice site	4	VUS (4)		0.000017
45.	c.821+1G>T		essential splice site	1		Likely Pathogenic (1)	0.000000
46.	c.821+1G>C		essential splice site	1	Pathogenic (1)		0.000000
47.	c.147_149delAGA	p.Glu51del	inframe	1	VUS (1)		0.000008
48.	c.487_489delGAG		inframe	14	Pathogenic (5)	Pathogenic (9)	0.000000
49.	c.678_680del	p.Glu226del	inframe	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. 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.