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