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.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
11.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
12.	c.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
13.	c.2146G>A	p.G716R	missense	7	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.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
17.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
18.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
19.	c.2681A>G	p.E894G	missense	4	Likely 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.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
23.	c.2717A>G	p.D906G	missense	4	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.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
27.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
28.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
29.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
30.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
31.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
32.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
33.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
34.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
35.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
36.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
37.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
38.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
39.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
40.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
41.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
42.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
43.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
44.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
45.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
46.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
47.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
48.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
49.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
50.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
51.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
52.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
53.	c.2623_2625delGAG	p.Glu875del	inframe	2	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.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
58.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
59.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
60.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
61.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
62.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
63.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
64.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
65.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
66.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
67.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
68.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
69.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
70.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
71.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
72.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
73.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
74.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
75.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
76.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
77.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
78.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
79.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
80.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
81.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
82.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
83.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
84.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
85.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
86.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
87.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
88.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
89.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
90.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
91.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
92.	c.137T>G	p.F46C	missense	1	VUS	0.000000
93.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
94.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
95.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
96.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
97.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
98.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
99.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
100.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
101.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
102.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
103.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
104.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
105.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
106.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
107.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
108.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
109.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
110.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
111.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
112.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
113.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
114.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
115.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
116.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
117.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
118.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
119.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
120.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
121.	c.115G>A	p.V39M	missense	1	VUS	0.000057
122.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
123.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
124.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
125.	c.1477_1478delAT		frameshift	1	VUS	0.000000
126.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
127.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
128.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
129.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
130.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
131.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
132.	c.976G>C	p.A326P	missense	1	VUS	0.000067
133.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
134.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
135.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
136.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
137.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
138.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
139.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
140.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
141.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
142.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
143.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
144.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
145.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
146.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
147.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
148.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
149.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
150.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
151.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
152.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
153.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
154.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
155.	c.135G>T	p.E45D	missense	1	VUS	0.000000
156.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
157.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
158.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
159.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
160.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
161.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
162.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
163.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
164.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
165.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
166.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
167.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
168.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
169.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
170.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
171.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
172.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
173.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
174.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
175.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
176.	c.632C>T	p.P211L	missense	1	VUS	0.000024
177.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
178.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
179.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
180.	c.968T>C	p.I323T	missense	1	VUS	0.000075
181.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
182.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
183.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
184.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
185.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
186.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
187.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
188.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
189.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
190.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
191.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
192.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
193.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
194.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
195.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
196.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
197.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
198.	c.2644C>G	p.Q882E	missense	1	VUS favour 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.