LMNA protein-altering variants in DCM cohorts

The table below lists the 46 rare (MAF<0.0001 in ExAC) protein-altering LMNA variants identified in a cohort of 1044 DCM patients (304 patients from OMGL, 740 patients from LMM). When this rare variant frequency of 0.04406 is compared with a background population rate of 0.00622, there is a statistically significant case excess of 0.03784 (p<0.0001), which suggests that approximately 40 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 (1044)▼	OMGL class	LMM class	ExAC frequency
1.	c.1442A>G	p.Y481C	missense	1		Likely Pathogenic (1)	0.000000
2.	c.436G>A	p.A146T	missense	1		VUS favour pathogenic (1)	0.000000
3.	c.976T>A	p.S326T	missense	1		Likely Pathogenic (1)	0.000059
4.	c.799T>C	p.Y267H	missense	1		Pathogenic (1)	0.000000
5.	c.1201C>T	p.R401C	missense	1		VUS (1)	0.000033
6.	c.1106T>C	p.L369P	missense	1		Likely Pathogenic (1)	0.000000
7.	c.863C>G	p.A288G	missense	1		Likely Pathogenic (1)	0.000000
8.	c.266G>A	p.R89H	missense	1		VUS (1)	0.000000
9.	c.1621C>T	p.R541C	missense	2		Likely Pathogenic (2)	0.000000
10.	c.1622G>A	p.R541H	missense	1	Likely Pathogenic (1)		0.000093
11.	c.448A>C	p.T150P	missense	1		Likely Pathogenic (1)	0.000000
12.	c.1003C>T	p.R335W	missense	3		Likely Pathogenic (3)	0.000000
13.	c.949G>A	p.E317K	missense	1		Likely Pathogenic (1)	0.000000
14.	c.1129C>T	p.R377C	missense	1		Likely Pathogenic (1)	0.000000
15.	c.356G>C	p.R119P	missense	1		Likely Pathogenic (1)	0.000000
16.	c.868G>A	p.E290K	missense	2	VUS (1)	VUS favour pathogenic (1)	0.000000
17.	c.481G>A	p.E161K	missense	2		Pathogenic (2)	0.000000
18.	c.350A>G	p.K117R	missense	1		VUS (1)	0.000068
19.	c.992G>A	p.R331Q	missense	1		Likely Pathogenic (1)	0.000016
20.	c.154C>G	p.L52V	missense	1		Likely Pathogenic (1)	0.000000
21.	c.175C>A	p.L59M	missense	1	VUS (1)		0.000000
22.	c.1412G>A	p.R471H	missense	1		Likely Pathogenic (1)	0.000000
23.	c.739G>A	p.E247K	missense	1		VUS (1)	0.000000
24.	c.1046G>A	p.R349Q	missense	1	VUS (1)		0.000000
25.	c.16C>T	p.Q6X	nonsense	1		Pathogenic (1)	0.000000
26.	c.673C>T	p.R225X	nonsense	2		Pathogenic (2)	0.000000
27.	c.961C>T	p.R321X	nonsense	3	Pathogenic (2)	Likely Pathogenic (1)	0.000000
28.	c.700C>T	p.Q234X	nonsense	1		Likely Pathogenic (1)	0.000000
29.	c.811-2A>C		essential splice site	1	Pathogenic (1)		0.000000
30.	c.356+2T>G		essential splice site	1	Pathogenic (1)		0.000000
31.	c.513+1G>C		essential splice site	1		Likely Pathogenic (1)	0.000000
32.	c.640-2A>G		essential splice site	1	Pathogenic (1)		0.000000
33.	c.1304_1307del	p.Arg435Leufs*44	frameshift	1	Pathogenic (1)		0.000000
34.	c.1526dupC	p.Thr510Tyrfs*42	frameshift	1		Likely Pathogenic (1)	0.000000
35.	c.970del	p.Glu324Argfs*156	frameshift	1	Pathogenic (1)		0.000000
36.	c.763delC		frameshift	1		Likely Pathogenic (1)	0.000000
37.	c.958delC		frameshift	1		Likely Pathogenic (1)	0.000000
38.	c.1111_1125del	p.Met371_Ala375del	inframe	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. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.