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