MYH7 variants in HCM cohorts

The table below lists the 438 rare (MAF<0.0001 in ExAC) protein-altering MYH7 variants identified in a cohort of 3200 HCM patients. When this rare variant frequency of 0.13687 is compared with a background population rate of 0.01398, there is a statistically significant case excess of 0.12289 (p<0.0001), which suggests that approximately 394 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.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.5135G>A	p.R1712Q	missense	8	VUS	0.000008
9.	c.2348G>A	p.R783H	missense	8	Likely Pathogenic	0.000016
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.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
17.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
18.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
19.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
20.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
21.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
22.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
23.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
24.	c.3475G>A	p.V1159M	missense	4	VUS	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.958G>A	p.V320M	missense	4	VUS	0.000008
28.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
29.	c.611G>A	p.R204H	missense	3	VUS	0.000000
30.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
31.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
32.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
33.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
34.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
35.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
36.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
37.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
38.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
39.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
40.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
41.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
42.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
43.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
44.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
45.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
46.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
47.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
48.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
49.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
50.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
51.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
52.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
53.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
54.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
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.1318G>A	p.V440M	missense	2	VUS	0.000000
58.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
59.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
60.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
61.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
62.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
63.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
64.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
65.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
66.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
67.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
68.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
69.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
70.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
71.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
72.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
73.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
74.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
75.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
76.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
77.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
78.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
79.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
80.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
81.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
82.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
83.	c.595G>A	p.A199T	missense	1	VUS	0.000000
84.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
85.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
86.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
87.	c.904C>A	p.L302M	missense	1	VUS	0.000000
88.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
89.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
90.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
91.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
92.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
93.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
94.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
95.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
96.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
97.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
98.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
99.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
100.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
101.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
102.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
103.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
104.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
105.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
106.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
107.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
108.	c.964T>A	p.S322T	missense	1	VUS	0.000000
109.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
110.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
111.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
112.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
113.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
114.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
115.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
116.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
117.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
118.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
119.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
120.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
121.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
122.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
123.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
124.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
125.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
126.	c.809A>G	p.K270R	missense	1	VUS	0.000000
127.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
128.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
129.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
130.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
131.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
132.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
133.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
134.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
135.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
136.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
137.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
138.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
139.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
140.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
141.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
142.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
143.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
144.	c.793A>T	p.T265S	missense	1	VUS	0.000000
145.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
146.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
147.	c.677C>T	p.A226V	missense	1	VUS	0.000000
148.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
149.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
150.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
151.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
152.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
153.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
154.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
155.	c.298G>A	p.A100T	missense	1	VUS	0.000016
156.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
157.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
158.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
159.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
160.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
161.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
162.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
163.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
164.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
165.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
166.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
167.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
168.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
169.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
170.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
171.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
172.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
173.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
174.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
175.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
176.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
177.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
178.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
179.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
180.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
181.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
182.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
183.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
184.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
185.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
186.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
187.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
188.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
189.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
190.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
191.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
192.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
193.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
194.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
195.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
196.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
197.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
198.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
199.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
200.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
201.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
202.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
203.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
204.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
205.	c.500C>T	p.T167I	missense	1	VUS	0.000000
206.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
207.	c.2069T>C	p.M690T	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.