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