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.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.611G>T	p.R204L	missense	4	VUS	0.000000
21.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
22.	c.715G>A	p.D239N	missense	4	Likely 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.2770G>A	p.E924K	missense	4	Pathogenic	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.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.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.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.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
50.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
51.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
52.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
53.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
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.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
58.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
59.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
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.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
66.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
67.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
68.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
69.	c.976G>C	p.A326P	missense	1	VUS	0.000067
70.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
71.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
72.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
73.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
74.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
75.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
76.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
77.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
78.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
79.	c.2502C>G	p.F834L	missense	1	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.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
87.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
88.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
89.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
90.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
91.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
92.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
93.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
94.	c.1969A>C	p.K657Q	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.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
98.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
99.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
100.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
101.	c.137T>G	p.F46C	missense	1	VUS	0.000000
102.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	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.2570C>T	p.T857I	missense	1	VUS	0.000000
107.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
108.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
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.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
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.4540G>A	p.E1514K	missense	1	VUS	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.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
120.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
121.	c.920C>T	p.P307L	missense	1	VUS favour 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.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
125.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
126.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
127.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
128.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
129.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
130.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
131.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
132.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
133.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
134.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
135.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
136.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
137.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
138.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
139.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
140.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
141.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
142.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
143.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
144.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
145.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
146.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
147.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
148.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
149.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
150.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
151.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
152.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
153.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
154.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
155.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
156.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
157.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
158.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
159.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
160.	c.135G>T	p.E45D	missense	1	VUS	0.000000
161.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
162.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
163.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
164.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
165.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
166.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
167.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
168.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
169.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
170.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
171.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
172.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
173.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
174.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
175.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
176.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
177.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
178.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
179.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
180.	c.293A>T	p.E98V	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.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
188.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
189.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
190.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
191.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
192.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
193.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
194.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
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.