MYH7 non-truncating variants in HCM cohorts

The table below lists the 434 rare (MAF<0.0001 in ExAC) non-truncating MYH7 variants identified in a cohort of 3200 HCM patients. When this rare variant frequency of 0.13562 is compared with a background population rate of 0.01350, there is a statistically significant case excess of 0.12212 (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 (3200)▼	OMGL class	ExAC frequency
1.	c.2389G>A	p.A797T	missense	24	Pathogenic	0.000032
2.	c.1988G>A	p.R663H	missense	17	Pathogenic	0.000016
3.	c.1816G>A	p.V606M	missense	13	Pathogenic	0.000000
4.	c.2609G>A	p.R870H	missense	13	Pathogenic	0.000000
5.	c.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
6.	c.1063G>A	p.A355T	missense	10	Likely Pathogenic	0.000000
7.	c.1357C>T	p.R453C	missense	10	Pathogenic	0.000000
8.	c.2348G>A	p.R783H	missense	8	Likely Pathogenic	0.000016
9.	c.5135G>A	p.R1712Q	missense	8	VUS	0.000008
10.	c.2221G>T	p.G741W	missense	8	Pathogenic	0.000000
11.	c.2717A>G	p.D906G	missense	7	Likely Pathogenic	0.000000
12.	c.2681A>G	p.E894G	missense	7	Likely Pathogenic	0.000000
13.	c.2207T>C	p.I736T	missense	6	Pathogenic	0.000000
14.	c.1207C>T	p.R403W	missense	6	Pathogenic	0.000000
15.	c.3158G>A	p.R1053Q	missense	6	Likely Pathogenic	0.000074
16.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
17.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
18.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
19.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
20.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
21.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
22.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
23.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
24.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
25.	c.958G>A	p.V320M	missense	4	VUS	0.000008
26.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
27.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
28.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
29.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
30.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
31.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
32.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
33.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
34.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
35.	c.611G>A	p.R204H	missense	3	VUS	0.000000
36.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
37.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
38.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
39.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
40.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
41.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
42.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
43.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
44.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
45.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
46.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
47.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
48.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
49.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
50.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
51.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
52.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
53.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
54.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
55.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
56.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
57.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
58.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
59.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
60.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
61.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
62.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
63.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
64.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
65.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
66.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
67.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
68.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
69.	c.809A>G	p.K270R	missense	1	VUS	0.000000
70.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
71.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
72.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
73.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
74.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
75.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
76.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
77.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
78.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
79.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
80.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
81.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
82.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
83.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
84.	c.500C>T	p.T167I	missense	1	VUS	0.000000
85.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
86.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
87.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
88.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
89.	c.595G>A	p.A199T	missense	1	VUS	0.000000
90.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
91.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
92.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
93.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
94.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
95.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
96.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
97.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
98.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
99.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
100.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
101.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
102.	c.298G>A	p.A100T	missense	1	VUS	0.000016
103.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
104.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
105.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
106.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
107.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
108.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
109.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
110.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
111.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
112.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
113.	c.904C>A	p.L302M	missense	1	VUS	0.000000
114.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
115.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
116.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
117.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
118.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
119.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
120.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
121.	c.964T>A	p.S322T	missense	1	VUS	0.000000
122.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
123.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
124.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
125.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
126.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
127.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
128.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
129.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
130.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
131.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
132.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
133.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
134.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
135.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
136.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
137.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
138.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
139.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
140.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
141.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
142.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
143.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
144.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
145.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
146.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
147.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
148.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
149.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
150.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
151.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
152.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
153.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
154.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
155.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
156.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
157.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
158.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
159.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
160.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
161.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
162.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
163.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
164.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
165.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
166.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
167.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
168.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
169.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
170.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
171.	c.793A>T	p.T265S	missense	1	VUS	0.000000
172.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
173.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
174.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
175.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
176.	c.677C>T	p.A226V	missense	1	VUS	0.000000
177.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
178.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
179.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
180.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
181.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
182.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
183.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
184.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
185.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
186.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
187.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
188.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
189.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
190.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
191.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
192.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
193.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
194.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
195.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
196.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
197.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
198.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
199.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
200.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
201.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
202.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
203.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
204.	c.5002A>G	p.K1668E	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.