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.470C>T	p.A157V	missense	11	Likely Pathogenic (3)	Pathogenic (8)	0.000000
4.	c.422G>A	p.R141Q	missense	11	Likely Pathogenic (6)	Likely Pathogenic (5)	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.428C>A	p.T143N	missense	3		VUS (3)	0.000024
12.	c.433C>G	p.R145G	missense	3	Pathogenic (2)	Pathogenic (1)	0.000000
13.	c.602T>C	p.M201T	missense	2	Likely Pathogenic (1)	Likely Pathogenic (1)	0.000000
14.	c.610C>T	p.R204C	missense	2		VUS favour pathogenic (2)	0.000000
15.	c.625G>A	p.E209K	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000000
16.	c.431T>C	p.L144P	missense	2	Likely Pathogenic (1)	Pathogenic (1)	0.000000
17.	c.596G>A	p.S199N	missense	2	Likely Pathogenic (2)		0.000000
18.	c.236G>T	p.R79L	missense	2		VUS (2)	0.000046
19.	c.575G>A	p.R192H	missense	2		Likely Pathogenic (2)	0.000000
20.	c.509G>A	p.R170Q	missense	2		Pathogenic (2)	0.000000
21.	c.590C>G	p.A197G	missense	1	VUS (1)		0.000000
22.	c.383T>A	p.L128Q	missense	1	VUS (1)		0.000000
23.	c.526G>A	p.V176M	missense	1		VUS favour pathogenic (1)	0.000000
24.	c.605A>C	p.E202A	missense	1	VUS (1)		0.000000
25.	c.167T>C	p.I56T	missense	1		VUS favour pathogenic (1)	0.000024
26.	c.488C>G	p.A163G	missense	1	VUS (1)		0.000000
27.	c.368C>T	p.T123M	missense	1		VUS (1)	0.000025
28.	c.607G>C	p.G203R	missense	1	Likely Pathogenic (1)		0.000000
29.	c.231C>A	p.S77R	missense	1	VUS (1)		0.000000
30.	c.512C>A	p.A171D	missense	1	VUS (1)		0.000000
31.	c.511G>A	p.A171T	missense	1	Likely Pathogenic (1)		0.000000
32.	c.593T>G	p.L198R	missense	1	VUS (1)		0.000000
33.	c.581A>C	p.N194T	missense	1	VUS (1)		0.000008
34.	c.379G>C	p.D127H	missense	1	VUS (1)		0.000000
35.	c.568G>T	p.D190Y	missense	1		Likely Pathogenic (1)	0.000000
36.	c.390G>C	p.Q130H	missense	1	VUS (1)		0.000000
37.	c.575G>T	p.R192L	missense	1		Likely Pathogenic (1)	0.000000
38.	c.389A>G	p.Q130R	missense	1	Likely Pathogenic (1)		0.000000
39.	c.592C>G	p.L198V	missense	1		VUS favour pathogenic (1)	0.000000
40.	c.439G>C	p.V147L	missense	1	VUS (1)		0.000008
41.	c.490A>G	p.K164E	missense	1	VUS (1)		0.000000
42.	c.497C>T	p.S166F	missense	1		VUS favour pathogenic (1)	0.000008
43.	c.532_534delAAG		inframe	1		Pathogenic (1)	0.000000
44.	c.626A>C	p.E209A	missense	1	Likely Pathogenic (1)		0.000000
45.	c.579G>C	p.K193N	missense	1		VUS favour pathogenic (1)	0.000000
46.	c.549G>C	p.K183N	missense	1	Likely Pathogenic (1)		0.000000
47.	c.532A>G	p.K178E	missense	1	Pathogenic (1)		0.000000
48.	c.285C>A	p.D95E	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.