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