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.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
2.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
3.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
4.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
5.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
6.	c.976G>C	p.A326P	missense	1	VUS	0.000067
7.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
8.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
9.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
10.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
11.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
12.	c.1207C>T	p.R403W	missense	4	Pathogenic	0.000000
13.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
14.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
15.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
16.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
17.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
18.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
19.	c.1816G>A	p.V606M	missense	9	Pathogenic	0.000000
20.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
21.	c.611G>T	p.R204L	missense	4	VUS	0.000000
22.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
23.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
24.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
25.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
26.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
27.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
28.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
29.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
30.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
31.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
32.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
33.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
34.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
35.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
36.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
37.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
38.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
39.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
40.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
41.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
42.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
43.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
44.	c.1357C>T	p.R453C	missense	13	Pathogenic	0.000000
45.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
46.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
47.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
48.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
49.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
50.	c.2146G>A	p.G716R	missense	7	Pathogenic	0.000000
51.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
52.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
53.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
54.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
55.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
56.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
57.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
58.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
59.	c.137T>G	p.F46C	missense	1	VUS	0.000000
60.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
61.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
62.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
63.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
64.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
65.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
66.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
67.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
68.	c.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
69.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
70.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
71.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
72.	c.632C>T	p.P211L	missense	1	VUS	0.000024
73.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
74.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
75.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
76.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
77.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
78.	c.968T>C	p.I323T	missense	1	VUS	0.000075
79.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
80.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
81.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
82.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
83.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
84.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
85.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
86.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
87.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
88.	c.1988G>A	p.R663H	missense	20	Pathogenic	0.000016
89.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
90.	c.2722C>G	p.L908V	missense	16	Pathogenic	0.000000
91.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
92.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
93.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
94.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
95.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
96.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
97.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
98.	c.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
99.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
100.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
101.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
102.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
103.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
104.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
105.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
106.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
107.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
108.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
109.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
110.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
111.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
112.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
113.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
114.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
115.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
116.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
117.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
118.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
119.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
120.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
121.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
122.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
123.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
124.	c.1208G>A	p.R403Q	missense	11	Pathogenic	0.000000
125.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
126.	c.2389G>A	p.A797T	missense	12	Pathogenic	0.000032
127.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
128.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
129.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
130.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
131.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
132.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
133.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
134.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
135.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
136.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
137.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
138.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
139.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
140.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
141.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
142.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	0.000000
143.	c.135G>T	p.E45D	missense	1	VUS	0.000000
144.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
145.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
146.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
147.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
148.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
149.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
150.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
151.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
152.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
153.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
154.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
155.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
156.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
157.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
158.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
159.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
160.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
161.	c.2156G>A	p.R719Q	missense	11	Pathogenic	0.000000
162.	c.1750G>C	p.G584R	missense	22	Likely Pathogenic	0.000000
163.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
164.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
165.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
166.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
167.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
168.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
169.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
170.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
171.	c.2167C>T	p.R723C	missense	9	Pathogenic	0.000024
172.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
173.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
174.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
175.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
176.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
177.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
178.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
179.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
180.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
181.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
182.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
183.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
184.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
185.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
186.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
187.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
188.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
189.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
190.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
191.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
192.	c.115G>A	p.V39M	missense	1	VUS	0.000057
193.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
194.	c.1477_1478delAT		frameshift	1	VUS	0.000000
195.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
196.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
197.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
198.	c.2623_2625delGAG	p.Glu875del	inframe	2	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.