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.2609G>A	p.R870H	missense	13	Pathogenic	0.000000
4.	c.1816G>A	p.V606M	missense	13	Pathogenic	0.000000
5.	c.1357C>T	p.R453C	missense	10	Pathogenic	0.000000
6.	c.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
7.	c.1063G>A	p.A355T	missense	10	Likely Pathogenic	0.000000
8.	c.2348G>A	p.R783H	missense	8	Likely Pathogenic	0.000016
9.	c.2221G>T	p.G741W	missense	8	Pathogenic	0.000000
10.	c.5135G>A	p.R1712Q	missense	8	VUS	0.000008
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.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.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
17.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
18.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
19.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
20.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
21.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
22.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
23.	c.958G>A	p.V320M	missense	4	VUS	0.000008
24.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
25.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
26.	c.3475G>A	p.V1159M	missense	4	VUS	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.1856C>T	p.T619I	missense	3	VUS	0.000033
30.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
31.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
32.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
33.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
34.	c.611G>A	p.R204H	missense	3	VUS	0.000000
35.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
36.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
37.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
38.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
39.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
40.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
41.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
42.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
43.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
44.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
45.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
46.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
47.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
48.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
49.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
50.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
51.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
52.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
53.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
54.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
55.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
56.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
57.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
58.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
59.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
60.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
61.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
62.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
63.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
64.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
65.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
66.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
67.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
68.	c.677C>T	p.A226V	missense	1	VUS	0.000000
69.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
70.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
71.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
72.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
73.	c.298G>A	p.A100T	missense	1	VUS	0.000016
74.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
75.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
76.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
77.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
78.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
79.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
80.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
81.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
82.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
83.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
84.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
85.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
86.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
87.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
88.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
89.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
90.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
91.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
92.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
93.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
94.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
95.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
96.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
97.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
98.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
99.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
100.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
101.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
102.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
103.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
104.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
105.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
106.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
107.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
108.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
109.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
110.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
111.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
112.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
113.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
114.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
115.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
116.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
117.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
118.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
119.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
120.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
121.	c.500C>T	p.T167I	missense	1	VUS	0.000000
122.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
123.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
124.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
125.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
126.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
127.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
128.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
129.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
130.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
131.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
132.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
133.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
134.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
135.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
136.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
137.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
138.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
139.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
140.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
141.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
142.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
143.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
144.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
145.	c.904C>A	p.L302M	missense	1	VUS	0.000000
146.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
147.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
148.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
149.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
150.	c.595G>A	p.A199T	missense	1	VUS	0.000000
151.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
152.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
153.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
154.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
155.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
156.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
157.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
158.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
159.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
160.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
161.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
162.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
163.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
164.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
165.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
166.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
167.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
168.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
169.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
170.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
171.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
172.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
173.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
174.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
175.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
176.	c.964T>A	p.S322T	missense	1	VUS	0.000000
177.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
178.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
179.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
180.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
181.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
182.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
183.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
184.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
185.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
186.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
187.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
188.	c.809A>G	p.K270R	missense	1	VUS	0.000000
189.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
190.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
191.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
192.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
193.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
194.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
195.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
196.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
197.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
198.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
199.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
200.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
201.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
202.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
203.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
204.	c.793A>T	p.T265S	missense	1	VUS	0.000000
205.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
206.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
207.	c.1207C>G	p.R403G	missense	1	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.