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.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
11.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
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.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
28.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
29.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
30.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
31.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
32.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
33.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
34.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
35.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
36.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
37.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
38.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
39.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
40.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
41.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
42.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
43.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
44.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
45.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
46.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
47.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
48.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
49.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
50.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
51.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
52.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
53.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
54.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
55.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
56.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
57.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
58.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
59.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
60.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
61.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
62.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
63.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
64.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
65.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
66.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
67.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
68.	c.632C>T	p.P211L	missense	1	VUS	0.000024
69.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
70.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
71.	c.968T>C	p.I323T	missense	1	VUS	0.000075
72.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
73.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
74.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
75.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
76.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
77.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
78.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
79.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
80.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
81.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
82.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
83.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
84.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
85.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
86.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
87.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
88.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
89.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
90.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
91.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
92.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
93.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
94.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
95.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
96.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
97.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
98.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
99.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
100.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
101.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
102.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
103.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
104.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
105.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
106.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
107.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
108.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
109.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
110.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
111.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
112.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
113.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
114.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
115.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
116.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
117.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
118.	c.135G>T	p.E45D	missense	1	VUS	0.000000
119.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
120.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
121.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
122.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
123.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
124.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
125.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
126.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
127.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
128.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
129.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
130.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
131.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
132.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
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.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
136.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
137.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
138.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
139.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
140.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
141.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
142.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
143.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
144.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
145.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
146.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
147.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
148.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
149.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
150.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
151.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
152.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
153.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
154.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
155.	c.1477_1478delAT		frameshift	1	VUS	0.000000
156.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
157.	c.115G>A	p.V39M	missense	1	VUS	0.000057
158.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
159.	c.976G>C	p.A326P	missense	1	VUS	0.000067
160.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
161.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
162.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
163.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
164.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
165.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
166.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
167.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
168.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
169.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
170.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
171.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
172.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
173.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
174.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
175.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
176.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
177.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
178.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
179.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
180.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
181.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
182.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
183.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
184.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
185.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
186.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
187.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
188.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
189.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
190.	c.137T>G	p.F46C	missense	1	VUS	0.000000
191.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
192.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
193.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
194.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
195.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
196.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
197.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
198.	c.1148A>G	p.K383R	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.