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