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.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.1490A>G	p.E497G	missense	1	Likely Pathogenic	0.000000
60.	c.1491G>T	p.E497D	missense	5	Likely Pathogenic	0.000000
61.	c.1496A>G	p.E499G	missense	1	VUS favour pathogenic	0.000000
62.	c.1499A>C	p.E500A	missense	1	VUS favour pathogenic	0.000000
63.	c.1514G>T	p.G505V	missense	1	VUS	0.000000
64.	c.1541G>A	p.G514D	missense	1	VUS	0.000000
65.	c.1549C>A	p.L517M	missense	1	VUS favour pathogenic	0.000000
66.	c.1562T>C	p.I521T	missense	1	Likely Pathogenic	0.000000
67.	c.1608G>T	p.E536D	missense	1	Likely Pathogenic	0.000000
68.	c.1727A>G	p.H576R	missense	2	Likely Pathogenic	0.000008
69.	c.1750G>C	p.G584R	missense	22	Likely Pathogenic	0.000000
70.	c.1757T>C	p.V586A	missense	2	Likely Pathogenic	0.000000
71.	c.1759G>A	p.D587N	missense	1	VUS favour pathogenic	0.000000
72.	c.1816G>A	p.V606M	missense	9	Pathogenic	0.000000
73.	c.1871A>G	p.Y624C	missense	1	VUS favour pathogenic	0.000000
74.	c.1969A>C	p.K657Q	missense	1	Likely Pathogenic	0.000000
75.	c.1987C>T	p.R663C	missense	8	Likely Pathogenic	0.000000
76.	c.1988G>A	p.R663H	missense	20	Pathogenic	0.000016
77.	c.2011C>T	p.R671C	missense	1	Likely Pathogenic	0.000000
78.	c.2052G>A	p.M684I	missense	1	VUS favour benign	0.000008
79.	c.2069T>C	p.M690T	missense	1	Pathogenic	0.000000
80.	c.2080C>T	p.R694C	missense	1	Likely Pathogenic	0.000016
81.	c.2101G>A	p.G701S	missense	1	VUS favour pathogenic	0.000000
82.	c.2105T>A	p.I702N	missense	1	Pathogenic	0.000000
83.	c.2123G>C	p.G708A	missense	1	Pathogenic	0.000000
84.	c.2129C>T	p.P710L	missense	1	Likely Pathogenic	0.000000
85.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
86.	c.2146G>A	p.G716R	missense	7	Pathogenic	0.000000
87.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
88.	c.2156G>A	p.R719Q	missense	11	Pathogenic	0.000000
89.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
90.	c.2167C>T	p.R723C	missense	9	Pathogenic	0.000024
91.	c.2178C>A	p.N726K	missense	1	VUS favour pathogenic	0.000000
92.	c.2191C>G	p.P731A	missense	1	Likely Pathogenic	0.000000
93.	c.2198G>A	p.G733E	missense	2	Likely Pathogenic	0.000000
94.	c.2206A>G	p.I736V	missense	1	VUS	0.000008
95.	c.2207T>C	p.I736T	missense	5	Likely Pathogenic	0.000000
96.	c.2217G>T	p.R739S	missense	1	Likely Pathogenic	0.000000
97.	c.2221G>T	p.G741W	missense	5	Pathogenic	0.000000
98.	c.2221G>A	p.G741R	missense	3	Pathogenic	0.000000
99.	c.2221G>C	p.G741R	missense	1	Pathogenic	0.000000
100.	c.2246T>A	p.L749Q	missense	1	Likely Pathogenic	0.000000
101.	c.2285A>G	p.K762R	missense	1	Pathogenic	0.000000
102.	c.2287G>A	p.V763M	missense	3	Likely Pathogenic	0.000000
103.	c.2296A>C	p.K766Q	missense	1	Pathogenic	0.000000
104.	c.2302G>A	p.G768R	missense	4	Likely Pathogenic	0.000000
105.	c.2342T>C	p.L781P	missense	1	Likely Pathogenic	0.000000
106.	c.2389G>A	p.A797T	missense	12	Pathogenic	0.000032
107.	c.2401T>A	p.Y801N	missense	1	VUS	0.000000
108.	c.2425G>T	p.D809Y	missense	1	VUS	0.000049
109.	c.2432T>C	p.L811P	missense	1	Likely Pathogenic	0.000000
110.	c.2462T>C	p.F821S	missense	1	VUS	0.000000
111.	c.2470G>C	p.V824L	missense	1	VUS favour pathogenic	0.000000
112.	c.2471T>C	p.V824A	missense	1	Likely Pathogenic	0.000000
113.	c.2498A>G	p.Y833C	missense	1	VUS	0.000000
114.	c.2502C>G	p.F834L	missense	1	Pathogenic	0.000000
115.	c.2525G>A	p.S842N	missense	1	Pathogenic	0.000000
116.	c.2539A>G	p.K847E	missense	4	Likely Pathogenic	0.000000
117.	c.2539_2541delAAG		inframe	3	Likely Pathogenic	0.000000
118.	c.2543A>G	p.E848G	missense	1	Likely Pathogenic	0.000000
119.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
120.	c.2555T>C	p.M852T	missense	1	VUS favour pathogenic	0.000000
121.	c.2570C>T	p.T857I	missense	1	VUS	0.000000
122.	c.2572C>G	p.R858G	missense	1	VUS	0.000000
123.	c.2572C>T	p.R858C	missense	1	VUS favour pathogenic	0.000000
124.	c.2602G>C	p.A868P	missense	1	Likely Pathogenic	0.000000
125.	c.2606G>A	p.R869H	missense	1	VUS favour pathogenic	0.000032
126.	c.2608C>T	p.R870C	missense	2	VUS	0.000008
127.	c.2609G>A	p.R870H	missense	3	Pathogenic	0.000000
128.	c.2623_2625delGAG	p.Glu875del	inframe	2	Pathogenic	0.000000
129.	c.2627_2629delAGA	p.Lys876del	inframe	1	VUS favour pathogenic	0.000000
130.	c.2644C>G	p.Q882E	missense	1	VUS favour pathogenic	0.000000
131.	c.2681A>G	p.E894G	missense	4	Likely Pathogenic	0.000000
132.	c.2692C>G	p.L898V	missense	1	Likely Pathogenic	0.000000
133.	c.2699A>G	p.D900G	missense	1	VUS favour pathogenic	0.000000
134.	c.2708A>G	p.E903G	missense	1	Likely Pathogenic	0.000000
135.	c.2716G>A	p.D906N	missense	1	VUS favour pathogenic	0.000000
136.	c.2717A>G	p.D906G	missense	4	Pathogenic	0.000000
137.	c.2719C>A	p.Q907K	missense	2	VUS	0.000000
138.	c.2722C>G	p.L908V	missense	16	Pathogenic	0.000000
139.	c.2725A>G	p.I909V	missense	1	VUS	0.000000
140.	c.2742G>T	p.Q914H	missense	1	Likely Pathogenic	0.000000
141.	c.2744T>C	p.L915P	missense	2	Pathogenic	0.000000
142.	c.2746G>A	p.E916K	missense	1	VUS favour pathogenic	0.000000
143.	c.2770G>A	p.E924K	missense	4	Pathogenic	0.000000
144.	c.2779G>A	p.E927K	missense	3	VUS favour pathogenic	0.000000
145.	c.2782G>A	p.D928N	missense	1	Likely Pathogenic	0.000000
146.	c.2783A>C	p.D928A	missense	1	VUS	0.000000
147.	c.2788G>C	p.E930Q	missense	2	Likely Pathogenic	0.000000
148.	c.2788G>A	p.E930K	missense	3	Pathogenic	0.000000
149.	c.2791_2793delGAG		inframe	1	Pathogenic	0.000000
150.	c.2845G>A	p.E949K	missense	1	Likely Pathogenic	0.000000
151.	c.2846A>T	p.E949V	missense	1	VUS favour pathogenic	0.000008
152.	c.2899G>A	p.E967K	missense	1	Likely Pathogenic	0.000000
153.	c.3133C>T	p.R1045C	missense	3	VUS favour pathogenic	0.000016
154.	c.3134G>T	p.R1045L	missense	2	Likely Pathogenic	0.000016
155.	c.3158G>A	p.R1053Q	missense	1	Likely Pathogenic	0.000074
156.	c.3169G>A	p.G1057S	missense	2	VUS favour pathogenic	0.000008
157.	c.3236G>A	p.R1079Q	missense	1	VUS	0.000008
158.	c.3346G>A	p.E1116K	missense	1	Likely Pathogenic	0.000000
159.	c.3626A>G	p.N1209S	missense	1	VUS	0.000000
160.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
161.	c.3664A>G	p.S1222G	missense	1	VUS favour pathogenic	0.000000
162.	c.3830G>A	p.R1277Q	missense	1	VUS	0.000041
163.	c.3967G>A	p.V1323I	missense	1	VUS favour benign	0.000000
164.	c.3994G>A	p.A1332T	missense	2	VUS favour pathogenic	0.000016
165.	c.4066G>A	p.E1356K	missense	1	Likely Pathogenic	0.000000
166.	c.4078G>A	p.V1360I	missense	1	VUS	0.000057
167.	c.4124A>G	p.Y1375C	missense	1	Likely Pathogenic	0.000000
168.	c.4130C>T	p.T1377M	missense	7	VUS favour pathogenic	0.000000
169.	c.4135G>A	p.A1379T	missense	2	Pathogenic	0.000000
170.	c.4136C>A	p.A1379D	missense	1	VUS favour pathogenic	0.000000
171.	c.4145G>A	p.R1382Q	missense	2	Likely Pathogenic	0.000000
172.	c.4156C>T	p.L1386F	missense	1	VUS favour pathogenic	0.000000
173.	c.4258C>T	p.R1420W	missense	1	VUS favour pathogenic	0.000008
174.	c.4259G>A	p.R1420Q	missense	1	VUS favour pathogenic	0.000000
175.	c.4283T>C	p.L1428S	missense	1	Likely Pathogenic	0.000032
176.	c.4436C>T	p.T1479I	missense	1	VUS favour pathogenic	0.000000
177.	c.4525A>C	p.I1509L	missense	1	VUS	0.000016
178.	c.4537A>T	p.T1513S	missense	2	VUS	0.000000
179.	c.4540G>A	p.E1514K	missense	1	VUS	0.000000
180.	c.4816C>T	p.R1606C	missense	1	Likely Pathogenic	0.000000
181.	c.4817G>A	p.R1606H	missense	3	VUS	0.000049
182.	c.4864C>T	p.L1622F	missense	1	VUS favour pathogenic	0.000000
183.	c.5020G>A	p.V1674M	missense	1	VUS	0.000024
184.	c.5135G>A	p.R1712Q	missense	8	Likely Pathogenic	0.000008
185.	c.5156A>G	p.Q1719R	missense	1	VUS favour pathogenic	0.000000
186.	c.5192A>T	p.D1731V	missense	1	VUS favour pathogenic	0.000000
187.	c.5287G>A	p.A1763T	missense	2	Likely Pathogenic	0.000041
188.	c.5326A>G	p.S1776G	missense	2	VUS favour pathogenic	0.000032
189.	c.5332C>T	p.H1778Y	missense	1	VUS	0.000000
190.	c.5341C>T	p.R1781C	missense	1	Pathogenic	0.000000
191.	c.5342G>A	p.R1781H	missense	2	Likely Pathogenic	0.000008
192.	c.5344A>G	p.M1782V	missense	1	Likely Pathogenic	0.000000
193.	c.5380C>A	p.Q1794K	missense	2	Likely Pathogenic	0.000000
194.	c.5561C>T	p.T1854M	missense	1	VUS favour pathogenic	0.000033
195.	c.5696T>C	p.V1899A	missense	1	VUS	0.000008
196.	c.5704G>C	p.E1902Q	missense	1	VUS favour pathogenic	0.000074
197.	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.