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