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