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