MYH7 non-truncating variants in HCM cohorts

The table below lists the 430 rare (MAF<0.0001 in ExAC) non-truncating MYH7 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.14766 is compared with a background population rate of 0.01350, there is a statistically significant case excess of 0.13416 (p<0.0001), which suggests that approximately 391 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 (2912)▼	LMM class	ExAC frequency
1.	c.1750G>C	p.G584R	missense	22	Likely Pathogenic	0.000000
2.	c.1988G>A	p.R663H	missense	20	Pathogenic	0.000016
3.	c.2722C>G	p.L908V	missense	16	Pathogenic	0.000000
4.	c.1357C>T	p.R453C	missense	13	Pathogenic	0.000000
5.	c.2389G>A	p.A797T	missense	12	Pathogenic	0.000032
6.	c.1208G>A	p.R403Q	missense	11	Pathogenic	0.000000
7.	c.2156G>A	p.R719Q	missense	11	Pathogenic	0.000000
8.	c.1816G>A	p.V606M	missense	9	Pathogenic	0.000000
9.	c.2167C>T	p.R723C	missense	9	Pathogenic	0.000024
10.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
11.	c.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
12.	c.2146G>A	p.G716R	missense	7	Pathogenic	0.000000
13.	c.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
14.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
15.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
16.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
17.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
18.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
19.	c.1207C>T	p.R403W	missense	4	Pathogenic	0.000000
20.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
21.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
22.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
23.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
24.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
25.	c.611G>T	p.R204L	missense	4	VUS	0.000000
26.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	0.000000
27.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
28.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
29.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
30.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
31.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
32.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
33.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
34.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
35.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
36.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
37.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
38.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
39.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
40.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
41.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
42.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
43.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
44.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
45.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
46.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
47.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
48.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
49.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
50.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
51.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
52.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
53.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
54.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
55.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
56.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
57.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
58.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
59.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
60.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
61.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
62.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
63.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
64.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
65.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
66.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
67.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
68.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
69.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
70.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
71.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
72.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
73.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
74.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
75.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
76.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
77.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
78.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
79.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
80.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
81.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
82.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
83.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
84.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
85.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
86.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
87.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
88.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
89.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
90.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
91.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
92.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
93.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
94.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
95.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
96.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
97.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
98.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
99.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
100.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
101.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
102.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
103.	c.135G>T	p.E45D	missense	1	VUS	0.000000
104.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
105.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
106.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
107.	c.632C>T	p.P211L	missense	1	VUS	0.000024
108.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
109.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
110.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
111.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
112.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
113.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
114.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
115.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
116.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
117.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
118.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
119.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
120.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
121.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
122.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
123.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
124.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
125.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
126.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
127.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
128.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
129.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
130.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
131.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
132.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
133.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
134.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
135.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
136.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
137.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
138.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
139.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
140.	c.976G>C	p.A326P	missense	1	VUS	0.000067
141.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
142.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
143.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
144.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
145.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
146.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
147.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
148.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
149.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
150.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
151.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
152.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
153.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
154.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
155.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
156.	c.137T>G	p.F46C	missense	1	VUS	0.000000
157.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
158.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
159.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
160.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
161.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
162.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
163.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
164.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
165.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
166.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
167.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
168.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
169.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
170.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
171.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
172.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
173.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
174.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
175.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
176.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
177.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
178.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
179.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
180.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
181.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
182.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
183.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
184.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
185.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
186.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
187.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
188.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
189.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
190.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
191.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
192.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
193.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
194.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
195.	c.968T>C	p.I323T	missense	1	VUS	0.000075
196.	c.115G>A	p.V39M	missense	1	VUS	0.000057
197.	c.4540G>A	p.E1514K	missense	1	VUS	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.