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