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