MYH7 variants in HCM cohorts

The table below lists the 431 rare (MAF<0.0001 in ExAC) protein-altering MYH7 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.14801 is compared with a background population rate of 0.01398, there is a statistically significant case excess of 0.13403 (p<0.0001), which suggests that approximately 392 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.2156G>A	p.R719Q	missense	11	Pathogenic	0.000000
7.	c.1208G>A	p.R403Q	missense	11	Pathogenic	0.000000
8.	c.2167C>T	p.R723C	missense	9	Pathogenic	0.000024
9.	c.1816G>A	p.V606M	missense	9	Pathogenic	0.000000
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.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
15.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
16.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
17.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
18.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
19.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	0.000000
20.	c.1207C>T	p.R403W	missense	4	Pathogenic	0.000000
21.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
22.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
23.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
24.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
25.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
26.	c.611G>T	p.R204L	missense	4	VUS	0.000000
27.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
28.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
29.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
30.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
31.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
32.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
33.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
34.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
35.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
36.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
37.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
38.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
39.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
40.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
41.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
42.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
43.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
44.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
45.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
46.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
47.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
48.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
49.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
50.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
51.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
52.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
53.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
54.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
55.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
56.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
57.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
58.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
59.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
60.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
61.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
62.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
63.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
64.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
65.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
66.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
67.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
68.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
69.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
70.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
71.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
72.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
73.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
74.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
75.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
76.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
77.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
78.	c.137T>G	p.F46C	missense	1	VUS	0.000000
79.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
80.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
81.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
82.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
83.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
84.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
85.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
86.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
87.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
88.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
89.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
90.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
91.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
92.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
93.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
94.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
95.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
96.	c.968T>C	p.I323T	missense	1	VUS	0.000075
97.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
98.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
99.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
100.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
101.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
102.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
103.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
104.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
105.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
106.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
107.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
108.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
109.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
110.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
111.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
112.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
113.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
114.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
115.	c.1477_1478delAT		frameshift	1	VUS	0.000000
116.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
117.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
118.	c.115G>A	p.V39M	missense	1	VUS	0.000057
119.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
120.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
121.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
122.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
123.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
124.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
125.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
126.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
127.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
128.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
129.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
130.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
131.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
132.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
133.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
134.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
135.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
136.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
137.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
138.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
139.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
140.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
141.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
142.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
143.	c.135G>T	p.E45D	missense	1	VUS	0.000000
144.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
145.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
146.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
147.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
148.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
149.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
150.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
151.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
152.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
153.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
154.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
155.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
156.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
157.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
158.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
159.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
160.	c.632C>T	p.P211L	missense	1	VUS	0.000024
161.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
162.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
163.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
164.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
165.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
166.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
167.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
168.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
169.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
170.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
171.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
172.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
173.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
174.	c.976G>C	p.A326P	missense	1	VUS	0.000067
175.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
176.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
177.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
178.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
179.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
180.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
181.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
182.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
183.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
184.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
185.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
186.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
187.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
188.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
189.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
190.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
191.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
192.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
193.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
194.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
195.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
196.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
197.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
198.	c.2791_2793delGAG		inframe	1	Pathogenic	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.