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.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.2221G>T	p.G741W	missense	8	Pathogenic	0.000000
9.	c.5135G>A	p.R1712Q	missense	8	VUS	0.000008
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.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.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
17.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
18.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
19.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
20.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
21.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
22.	c.2722C>G	p.L908V	missense	5	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.3475G>A	p.V1159M	missense	4	VUS	0.000000
26.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
27.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
28.	c.958G>A	p.V320M	missense	4	VUS	0.000008
29.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
30.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
31.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
32.	c.611G>A	p.R204H	missense	3	VUS	0.000000
33.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
34.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	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.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
40.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
41.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
42.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
43.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
44.	c.1051A>G	p.K351E	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.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
48.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
49.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
50.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
51.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
52.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
53.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
54.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
55.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
56.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
57.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
58.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
59.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
60.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
61.	c.578A>G	p.Q193R	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.4259G>T	p.R1420L	missense	2	VUS	0.000000
65.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
66.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
67.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
68.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
69.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
70.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
71.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
72.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
73.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
74.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
75.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
76.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
77.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
78.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
79.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
80.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
81.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
82.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
83.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
84.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
85.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
86.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
87.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
88.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
89.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
90.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
91.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
92.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
93.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
94.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
95.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
96.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
97.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
98.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
99.	c.500C>T	p.T167I	missense	1	VUS	0.000000
100.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
101.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
102.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
103.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
104.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
105.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
106.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
107.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
108.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
109.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
110.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
111.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
112.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
113.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
114.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
115.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
116.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
117.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
118.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
119.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
120.	c.595G>A	p.A199T	missense	1	VUS	0.000000
121.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
122.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
123.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
124.	c.904C>A	p.L302M	missense	1	VUS	0.000000
125.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
126.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
127.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
128.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
129.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
130.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
131.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
132.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
133.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
134.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
135.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
136.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
137.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
138.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
139.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
140.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
141.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
142.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
143.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
144.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
145.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
146.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
147.	c.964T>A	p.S322T	missense	1	VUS	0.000000
148.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
149.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
150.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
151.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
152.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
153.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
154.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
155.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
156.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
157.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
158.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
159.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
160.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
161.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
162.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
163.	c.809A>G	p.K270R	missense	1	VUS	0.000000
164.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
165.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
166.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
167.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
168.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
169.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
170.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
171.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
172.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
173.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
174.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
175.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
176.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
177.	c.793A>T	p.T265S	missense	1	VUS	0.000000
178.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
179.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
180.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
181.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
182.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
183.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
184.	c.677C>T	p.A226V	missense	1	VUS	0.000000
185.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
186.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
187.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
188.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
189.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
190.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
191.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
192.	c.298G>A	p.A100T	missense	1	VUS	0.000016
193.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
194.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
195.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
196.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
197.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
198.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
199.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
200.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
201.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
202.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
203.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
204.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
205.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
206.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
207.	c.3622G>A	p.D1208N	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.