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