MYH7 non-truncating variants in HCM cohorts

The table below lists the 430 rare (MAF<0.0001 in ExAC) non-truncating MYH7 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.14766 is compared with a background population rate of 0.01350, there is a statistically significant case excess of 0.13416 (p<0.0001), which suggests that approximately 391 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.428G>A	p.R143Q	missense	5	Likely Pathogenic	0.000008
15.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
16.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
17.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
18.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
19.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
20.	c.715G>A	p.D239N	missense	4	Likely Pathogenic	0.000000
21.	c.1207C>T	p.R403W	missense	4	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.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
27.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
28.	c.1063G>A	p.A355T	missense	3	VUS favour pathogenic	0.000000
29.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
30.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
31.	c.788T>C	p.I263T	missense	3	Likely Pathogenic	0.000000
32.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
33.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
34.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
35.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
36.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
37.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
38.	c.1318G>A	p.V440M	missense	2	Likely Pathogenic	0.000000
39.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
40.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
41.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
42.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
43.	c.1358G>A	p.R453H	missense	2	Likely Pathogenic	0.000000
44.	c.872C>T	p.S291F	missense	2	Likely Pathogenic	0.000000
45.	c.28G>C	p.G10R	missense	2	VUS favour pathogenic	0.000074
46.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
47.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
48.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
49.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
50.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
51.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
52.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
53.	c.1283C>T	p.A428V	missense	2	VUS favour pathogenic	0.000000
54.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
55.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
56.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
57.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
58.	c.49C>T	p.R17C	missense	2	Likely Pathogenic	0.000000
59.	c.1003G>T	p.A335S	missense	2	VUS favour pathogenic	0.000000
60.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
61.	c.596C>T	p.A199V	missense	2	Likely Pathogenic	0.000000
62.	c.1012G>A	p.V338M	missense	2	Likely Pathogenic	0.000000
63.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
64.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
65.	c.1148A>G	p.K383R	missense	1	VUS	0.000000
66.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
67.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
68.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
69.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
70.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
71.	c.1357C>A	p.R453S	missense	1	Likely Pathogenic	0.000000
72.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
73.	c.739T>C	p.F247L	missense	1	Likely Pathogenic	0.000000
74.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
75.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
76.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
77.	c.343T>C	p.Y115H	missense	1	Pathogenic	0.000008
78.	c.727C>T	p.R243C	missense	1	VUS favour pathogenic	0.000000
79.	c.1315A>T	p.M439L	missense	1	VUS favour pathogenic	0.000016
80.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
81.	c.968T>C	p.I323T	missense	1	VUS	0.000075
82.	c.115G>A	p.V39M	missense	1	VUS	0.000057
83.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
84.	c.161G>A	p.R54Q	missense	1	VUS	0.000016
85.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
86.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
87.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
88.	c.920C>T	p.P307L	missense	1	VUS favour pathogenic	0.000000
89.	c.506G>A	p.R169K	missense	1	Likely Pathogenic	0.000000
90.	c.427C>T	p.R143W	missense	1	VUS favour pathogenic	0.000049
91.	c.707T>C	p.V236A	missense	1	VUS favour pathogenic	0.000000
92.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
93.	c.1166G>A	p.G389E	missense	1	VUS favour pathogenic	0.000000
94.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
95.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
96.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
97.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
98.	c.619A>C	p.K207Q	missense	1	VUS favour pathogenic	0.000000
99.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
100.	c.1426C>G	p.L476V	missense	1	VUS	0.000000
101.	c.438G>T	p.K146N	missense	1	Likely Pathogenic	0.000000
102.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
103.	c.1157A>G	p.Y386C	missense	1	Likely Pathogenic	0.000000
104.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
105.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
106.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
107.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
108.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
109.	c.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
110.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
111.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
112.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
113.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
114.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
115.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
116.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
117.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
118.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
119.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
120.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
121.	c.135G>T	p.E45D	missense	1	VUS	0.000000
122.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
123.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
124.	c.505A>G	p.R169G	missense	1	Likely Pathogenic	0.000000
125.	c.1405G>A	p.D469N	missense	1	VUS favour pathogenic	0.000008
126.	c.632C>T	p.P211L	missense	1	VUS	0.000024
127.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
128.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
129.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
130.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
131.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
132.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
133.	c.743T>C	p.I248T	missense	1	Likely Pathogenic	0.000000
134.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
135.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
136.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
137.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
138.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
139.	c.830T>C	p.L277P	missense	1	VUS favour pathogenic	0.000000
140.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
141.	c.293A>T	p.E98V	missense	1	VUS favour pathogenic	0.000000
142.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
143.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
144.	c.1132A>C	p.T378P	missense	1	VUS	0.000000
145.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
146.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
147.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
148.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
149.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
150.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
151.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
152.	c.968T>A	p.I323N	missense	1	Likely Pathogenic	0.000000
153.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
154.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
155.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
156.	c.1013T>C	p.V338A	missense	1	VUS	0.000000
157.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
158.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
159.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
160.	c.976G>C	p.A326P	missense	1	VUS	0.000067
161.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
162.	c.5749G>T	p.V1917F	missense	1	VUS favour pathogenic	0.000000
163.	c.746G>A	p.R249Q	missense	1	Pathogenic	0.000000
164.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
165.	c.748A>G	p.I250V	missense	1	VUS favour pathogenic	0.000000
166.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
167.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
168.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
169.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
170.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
171.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
172.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
173.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
174.	c.1352A>C	p.Q451P	missense	1	VUS	0.000000
175.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
176.	c.137T>G	p.F46C	missense	1	VUS	0.000000
177.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
178.	c.1324C>T	p.R442C	missense	1	Pathogenic	0.000008
179.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
180.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
181.	c.1220G>T	p.G407V	missense	1	VUS	0.000000
182.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
183.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
184.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
185.	c.1060G>A	p.G354S	missense	1	Likely Pathogenic	0.000000
186.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
187.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
188.	c.848A>G	p.Y283C	missense	1	Likely Pathogenic	0.000000
189.	c.507A>T	p.R169S	missense	1	Likely Pathogenic	0.000000
190.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
191.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
192.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
193.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
194.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
195.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
196.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
197.	c.2101G>A	p.G701S	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.