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.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
13.	c.2146G>A	p.G716R	missense	7	Pathogenic	0.000000
14.	c.2207T>C	p.I736T	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.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
18.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
19.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
20.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
21.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
22.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
23.	c.611G>T	p.R204L	missense	4	VUS	0.000000
24.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
25.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	0.000000
26.	c.1207C>T	p.R403W	missense	4	Pathogenic	0.000000
27.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
28.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
29.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
30.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
31.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
32.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
33.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
34.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
35.	c.788T>C	p.I263T	missense	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.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
39.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
40.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
41.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
42.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
43.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
44.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
45.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
46.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
47.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
48.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
49.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
50.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
51.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
52.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
53.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
54.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
55.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
56.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
57.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
58.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
59.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
60.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
61.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
62.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
63.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
64.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
65.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
66.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
67.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
68.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
69.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
70.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
71.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
72.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
73.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
74.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
75.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
76.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
77.	c.135G>T	p.E45D	missense	1	VUS	0.000000
78.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
79.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
80.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
81.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
82.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
83.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
84.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
85.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
86.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
87.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
88.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
89.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
90.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
91.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
92.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
93.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
94.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
95.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
96.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
97.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
98.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
99.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
100.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
101.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
102.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
103.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
104.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
105.	c.1477_1478delAT		frameshift	1	VUS	0.000000
106.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
107.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
108.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
109.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
110.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
111.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
112.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
113.	c.976G>C	p.A326P	missense	1	VUS	0.000067
114.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
115.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
116.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
117.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
118.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
119.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
120.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
121.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
122.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
123.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
124.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
125.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
126.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
127.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
128.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
129.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
130.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
131.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
132.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
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.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
136.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
137.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
138.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
139.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
140.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
141.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
142.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
143.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
144.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
145.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
146.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
147.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
148.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
149.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
150.	c.137T>G	p.F46C	missense	1	VUS	0.000000
151.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
152.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
153.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
154.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
155.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
156.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
157.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
158.	c.632C>T	p.P211L	missense	1	VUS	0.000024
159.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
160.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
161.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
162.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
163.	c.968T>C	p.I323T	missense	1	VUS	0.000075
164.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
165.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
166.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
167.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
168.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
169.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
170.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
171.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
172.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
173.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
174.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
175.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
176.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
177.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
178.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
179.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
180.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
181.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
182.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
183.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
184.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
185.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
186.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
187.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
188.	c.115G>A	p.V39M	missense	1	VUS	0.000057
189.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
190.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
191.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
192.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
193.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
194.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
195.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
196.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
197.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
198.	c.1490A>G	p.E497G	missense	1	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.