MYH7 protein-altering 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.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
11.	c.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
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.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
15.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
16.	c.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
17.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
18.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
19.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
20.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
21.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
22.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
23.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
24.	c.611G>T	p.R204L	missense	4	VUS	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.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
28.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
29.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
30.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
31.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
32.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
33.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
34.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
35.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
36.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
37.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
38.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
39.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
40.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
41.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
42.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
43.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
44.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
45.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
46.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
47.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
48.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
49.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
50.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
51.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
52.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
53.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
54.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
55.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
56.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
57.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
58.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
59.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
60.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
61.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
62.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
63.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
64.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
65.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
66.	c.137T>G	p.F46C	missense	1	VUS	0.000000
67.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
68.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
69.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
70.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
71.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
72.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
73.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
74.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
75.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
76.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
77.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
78.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
79.	c.968T>C	p.I323T	missense	1	VUS	0.000075
80.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
81.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
82.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
83.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
84.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
85.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
86.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
87.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
88.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
89.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
90.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
91.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
92.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
93.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
94.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
95.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
96.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
97.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
98.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
99.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
100.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
101.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
102.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
103.	c.1477_1478delAT		frameshift	1	VUS	0.000000
104.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
105.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
106.	c.115G>A	p.V39M	missense	1	VUS	0.000057
107.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
108.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
109.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
110.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
111.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
112.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
113.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
114.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
115.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
116.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
117.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
118.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
119.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
120.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
121.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
122.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
123.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
124.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
125.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
126.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
127.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
128.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
129.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
130.	c.135G>T	p.E45D	missense	1	VUS	0.000000
131.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
132.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
133.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
134.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
135.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
136.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
137.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
138.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
139.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
140.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
141.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
142.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
143.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
144.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
145.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
146.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
147.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
148.	c.632C>T	p.P211L	missense	1	VUS	0.000024
149.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
150.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
151.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
152.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
153.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
154.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
155.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
156.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
157.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
158.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
159.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
160.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
161.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
162.	c.976G>C	p.A326P	missense	1	VUS	0.000067
163.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
164.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
165.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
166.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
167.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
168.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
169.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
170.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
171.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
172.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
173.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
174.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
175.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
176.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
177.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
178.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
179.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
180.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
181.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
182.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
183.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
184.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
185.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
186.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
187.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
188.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
189.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
190.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
191.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
192.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
193.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
194.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
195.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
196.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
197.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
198.	c.2742G>T	p.Q914H	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.