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.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
2.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
3.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
4.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
5.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
6.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
7.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
8.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
9.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
10.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
11.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
12.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
13.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
14.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
15.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
16.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
17.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
18.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
19.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
20.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
21.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
22.	c.2722C>G	p.L908V	missense	16	Pathogenic	0.000000
23.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
24.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
25.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
26.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
27.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
28.	c.1208G>A	p.R403Q	missense	11	Pathogenic	0.000000
29.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
30.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
31.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
32.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
33.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
34.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
35.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
36.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
37.	c.135G>T	p.E45D	missense	1	VUS	0.000000
38.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
39.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
40.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
41.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
42.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
43.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	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.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
47.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
48.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
49.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
50.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
51.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
52.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
53.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
54.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
55.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
56.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
57.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
58.	c.1750G>C	p.G584R	missense	22	Likely Pathogenic	0.000000
59.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
60.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
61.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
62.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
63.	c.2389G>A	p.A797T	missense	12	Pathogenic	0.000032
64.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
65.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
66.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
67.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
68.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
69.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
70.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
71.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
72.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
73.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
74.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
75.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
76.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
77.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
78.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
79.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
80.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
81.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
82.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
83.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
84.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
85.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
86.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
87.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
88.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
89.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
90.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
91.	c.115G>A	p.V39M	missense	1	VUS	0.000057
92.	c.2156G>A	p.R719Q	missense	11	Pathogenic	0.000000
93.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
94.	c.976G>C	p.A326P	missense	1	VUS	0.000067
95.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
96.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
97.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
98.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
99.	c.2167C>T	p.R723C	missense	9	Pathogenic	0.000024
100.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
101.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
102.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
103.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
104.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
105.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
106.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
107.	c.611G>T	p.R204L	missense	4	VUS	0.000000
108.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
109.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
110.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
111.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
112.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
113.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
114.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
115.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
116.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
117.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
118.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
119.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
120.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
121.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
122.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
123.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
124.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
125.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
126.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
127.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
128.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
129.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
130.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
131.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
132.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
133.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
134.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
135.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
136.	c.1207C>T	p.R403W	missense	4	Pathogenic	0.000000
137.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
138.	c.1357C>T	p.R453C	missense	13	Pathogenic	0.000000
139.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
140.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
141.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
142.	c.1816G>A	p.V606M	missense	9	Pathogenic	0.000000
143.	c.137T>G	p.F46C	missense	1	VUS	0.000000
144.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
145.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
146.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
147.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
148.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
149.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
150.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
151.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
152.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
153.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
154.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
155.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
156.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
157.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
158.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
159.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
160.	c.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
161.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
162.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
163.	c.632C>T	p.P211L	missense	1	VUS	0.000024
164.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
165.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
166.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
167.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
168.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
169.	c.968T>C	p.I323T	missense	1	VUS	0.000075
170.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
171.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
172.	c.2146G>A	p.G716R	missense	7	Pathogenic	0.000000
173.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
174.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
175.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
176.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
177.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
178.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
179.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
180.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
181.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
182.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
183.	c.1988G>A	p.R663H	missense	20	Pathogenic	0.000016
184.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
185.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
186.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
187.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
188.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
189.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
190.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
191.	c.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
192.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
193.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
194.	c.1477_1478delAT		frameshift	1	VUS	0.000000
195.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
196.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
197.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
198.	c.2539_2541delAAG		inframe	3	Likely 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.