TNNI3 non-truncating variants in HCM cohorts

The table below lists the 129 rare (MAF<0.0001 in ExAC) non-truncating TNNI3 variants identified in a cohort of 6047 HCM patients (3135 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.02133 is compared with a background population rate of 0.00186, there is a statistically significant case excess of 0.01947 (p<0.0001), which suggests that approximately 117 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 (6047)▼	OMGL class	LMM class	ExAC frequency
1.	c.167T>C	p.I56T	missense	1		VUS favour pathogenic (1)	0.000024
2.	c.231C>A	p.S77R	missense	1	VUS (1)		0.000000
3.	c.236G>T	p.R79L	missense	2		VUS (2)	0.000046
4.	c.285C>A	p.D95E	missense	1	VUS (1)		0.000000
5.	c.368C>T	p.T123M	missense	1		VUS (1)	0.000025
6.	c.379G>C	p.D127H	missense	1	VUS (1)		0.000000
7.	c.383T>A	p.L128Q	missense	1	VUS (1)		0.000000
8.	c.389A>G	p.Q130R	missense	1	Likely Pathogenic (1)		0.000000
9.	c.390G>C	p.Q130H	missense	1	VUS (1)		0.000000
10.	c.407G>A	p.R136Q	missense	3	Likely Pathogenic (3)		0.000008
11.	c.422G>A	p.R141Q	missense	11	Likely Pathogenic (6)	Likely Pathogenic (5)	0.000000
12.	c.428C>A	p.T143N	missense	3		VUS (3)	0.000024
13.	c.431T>C	p.L144P	missense	2	Likely Pathogenic (1)	Pathogenic (1)	0.000000
14.	c.433C>T	p.R145W	missense	13	Pathogenic (10)	Pathogenic (3)	0.000008
15.	c.433C>G	p.R145G	missense	3	Pathogenic (2)	Pathogenic (1)	0.000000
16.	c.434G>A	p.R145Q	missense	4		Likely Pathogenic (4)	0.000024
17.	c.439G>C	p.V147L	missense	1	VUS (1)		0.000008
18.	c.470C>T	p.A157V	missense	11	Likely Pathogenic (3)	Pathogenic (8)	0.000000
19.	c.484C>T	p.R162W	missense	9	VUS (7)	VUS (2)	0.000033
20.	c.485G>C	p.R162P	missense	1		Likely Pathogenic (1)	0.000000
21.	c.485G>A	p.R162Q	missense	12	VUS (4)	Likely Pathogenic (8)	0.000024
22.	c.488C>G	p.A163G	missense	1	VUS (1)		0.000000
23.	c.490A>G	p.K164E	missense	1	VUS (1)		0.000000
24.	c.497C>T	p.S166F	missense	1		VUS favour pathogenic (1)	0.000008
25.	c.509G>A	p.R170Q	missense	2		Pathogenic (2)	0.000000
26.	c.511G>A	p.A171T	missense	1	Likely Pathogenic (1)		0.000000
27.	c.512C>A	p.A171D	missense	1	VUS (1)		0.000000
28.	c.526G>A	p.V176M	missense	1		VUS favour pathogenic (1)	0.000000
29.	c.532_534delAAG		inframe	1		Pathogenic (1)	0.000000
30.	c.532A>G	p.K178E	missense	1	Pathogenic (1)		0.000000
31.	c.549G>C	p.K183N	missense	1	Likely Pathogenic (1)		0.000000
32.	c.557G>A	p.R186Q	missense	5	Pathogenic (2)	Pathogenic (3)	0.000000
33.	c.568G>T	p.D190Y	missense	1		Likely Pathogenic (1)	0.000000
34.	c.575G>A	p.R192H	missense	2		Likely Pathogenic (2)	0.000000
35.	c.575G>T	p.R192L	missense	1		Likely Pathogenic (1)	0.000000
36.	c.579G>C	p.K193N	missense	1		VUS favour pathogenic (1)	0.000000
37.	c.581A>C	p.N194T	missense	1	VUS (1)		0.000008
38.	c.586G>A	p.D196N	missense	6	Likely Pathogenic (4)	VUS favour pathogenic (2)	0.000008
39.	c.590C>G	p.A197G	missense	1	VUS (1)		0.000000
40.	c.592C>G	p.L198V	missense	1		VUS favour pathogenic (1)	0.000000
41.	c.593T>G	p.L198R	missense	1	VUS (1)		0.000000
42.	c.596G>A	p.S199N	missense	2	Likely Pathogenic (2)		0.000000
43.	c.602T>C	p.M201T	missense	2	Likely Pathogenic (1)	Likely Pathogenic (1)	0.000000
44.	c.605A>C	p.E202A	missense	1	VUS (1)		0.000000
45.	c.607G>C	p.G203R	missense	1	Likely Pathogenic (1)		0.000000
46.	c.610C>T	p.R204C	missense	2		VUS favour pathogenic (2)	0.000000
47.	c.611G>A	p.R204H	missense	4	Likely Pathogenic (1)	Likely Pathogenic (3)	0.000000
48.	c.625G>A	p.E209K	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000000
49.	c.626A>C	p.E209A	missense	1	Likely 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. 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.