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

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.