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.433C>T	p.R145W	missense	13	Pathogenic (10)	Pathogenic (3)	0.000008
2.	c.485G>A	p.R162Q	missense	12	VUS (4)	Likely Pathogenic (8)	0.000024
3.	c.422G>A	p.R141Q	missense	11	Likely Pathogenic (6)	Likely Pathogenic (5)	0.000000
4.	c.470C>T	p.A157V	missense	11	Likely Pathogenic (3)	Pathogenic (8)	0.000000
5.	c.484C>T	p.R162W	missense	9	VUS (7)	VUS (2)	0.000033
6.	c.586G>A	p.D196N	missense	6	Likely Pathogenic (4)	VUS favour pathogenic (2)	0.000008
7.	c.557G>A	p.R186Q	missense	5	Pathogenic (2)	Pathogenic (3)	0.000000
8.	c.611G>A	p.R204H	missense	4	Likely Pathogenic (1)	Likely Pathogenic (3)	0.000000
9.	c.434G>A	p.R145Q	missense	4		Likely Pathogenic (4)	0.000024
10.	c.407G>A	p.R136Q	missense	3	Likely Pathogenic (3)		0.000008
11.	c.433C>G	p.R145G	missense	3	Pathogenic (2)	Pathogenic (1)	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.596G>A	p.S199N	missense	2	Likely Pathogenic (2)		0.000000
15.	c.236G>T	p.R79L	missense	2		VUS (2)	0.000046
16.	c.509G>A	p.R170Q	missense	2		Pathogenic (2)	0.000000
17.	c.602T>C	p.M201T	missense	2	Likely Pathogenic (1)	Likely Pathogenic (1)	0.000000
18.	c.625G>A	p.E209K	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000000
19.	c.610C>T	p.R204C	missense	2		VUS favour pathogenic (2)	0.000000
20.	c.575G>A	p.R192H	missense	2		Likely Pathogenic (2)	0.000000
21.	c.575G>T	p.R192L	missense	1		Likely Pathogenic (1)	0.000000
22.	c.389A>G	p.Q130R	missense	1	Likely Pathogenic (1)		0.000000
23.	c.592C>G	p.L198V	missense	1		VUS favour pathogenic (1)	0.000000
24.	c.490A>G	p.K164E	missense	1	VUS (1)		0.000000
25.	c.439G>C	p.V147L	missense	1	VUS (1)		0.000008
26.	c.497C>T	p.S166F	missense	1		VUS favour pathogenic (1)	0.000008
27.	c.532_534delAAG		inframe	1		Pathogenic (1)	0.000000
28.	c.626A>C	p.E209A	missense	1	Likely Pathogenic (1)		0.000000
29.	c.549G>C	p.K183N	missense	1	Likely Pathogenic (1)		0.000000
30.	c.532A>G	p.K178E	missense	1	Pathogenic (1)		0.000000
31.	c.285C>A	p.D95E	missense	1	VUS (1)		0.000000
32.	c.579G>C	p.K193N	missense	1		VUS favour pathogenic (1)	0.000000
33.	c.590C>G	p.A197G	missense	1	VUS (1)		0.000000
34.	c.383T>A	p.L128Q	missense	1	VUS (1)		0.000000
35.	c.526G>A	p.V176M	missense	1		VUS favour pathogenic (1)	0.000000
36.	c.605A>C	p.E202A	missense	1	VUS (1)		0.000000
37.	c.167T>C	p.I56T	missense	1		VUS favour pathogenic (1)	0.000024
38.	c.488C>G	p.A163G	missense	1	VUS (1)		0.000000
39.	c.607G>C	p.G203R	missense	1	Likely Pathogenic (1)		0.000000
40.	c.368C>T	p.T123M	missense	1		VUS (1)	0.000025
41.	c.231C>A	p.S77R	missense	1	VUS (1)		0.000000
42.	c.512C>A	p.A171D	missense	1	VUS (1)		0.000000
43.	c.511G>A	p.A171T	missense	1	Likely Pathogenic (1)		0.000000
44.	c.581A>C	p.N194T	missense	1	VUS (1)		0.000008
45.	c.379G>C	p.D127H	missense	1	VUS (1)		0.000000
46.	c.568G>T	p.D190Y	missense	1		Likely Pathogenic (1)	0.000000
47.	c.593T>G	p.L198R	missense	1	VUS (1)		0.000000
48.	c.390G>C	p.Q130H	missense	1	VUS (1)		0.000000
49.	c.485G>C	p.R162P	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.