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

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.