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.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.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
20.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
21.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
22.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
23.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
24.	c.958G>A	p.V320M	missense	4	VUS	0.000008
25.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
26.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
27.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
28.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
29.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
30.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
31.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
32.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
33.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
34.	c.611G>A	p.R204H	missense	3	VUS	0.000000
35.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
36.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
37.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
38.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
39.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
40.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
41.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
42.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
43.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
44.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
45.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
46.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
47.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
48.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
49.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
50.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
51.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
52.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
53.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
54.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
55.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
56.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
57.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
58.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
59.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
60.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
61.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
62.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
63.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
64.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
65.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
66.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
67.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
68.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
69.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
70.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
71.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
72.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
73.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
74.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
75.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
76.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
77.	c.809A>G	p.K270R	missense	1	VUS	0.000000
78.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
79.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
80.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
81.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
82.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
83.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
84.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
85.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
86.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
87.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
88.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
89.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
90.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
91.	c.793A>T	p.T265S	missense	1	VUS	0.000000
92.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
93.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
94.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
95.	c.677C>T	p.A226V	missense	1	VUS	0.000000
96.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
97.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
98.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
99.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
100.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
101.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
102.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
103.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
104.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
105.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
106.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
107.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
108.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
109.	c.298G>A	p.A100T	missense	1	VUS	0.000016
110.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
111.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
112.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
113.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
114.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
115.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
116.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
117.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
118.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
119.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
120.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
121.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
122.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
123.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
124.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
125.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
126.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
127.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
128.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
129.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
130.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
131.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
132.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
133.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
134.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
135.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
136.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
137.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
138.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
139.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
140.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
141.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
142.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
143.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
144.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
145.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
146.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
147.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
148.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
149.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
150.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
151.	c.500C>T	p.T167I	missense	1	VUS	0.000000
152.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
153.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
154.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
155.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
156.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
157.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
158.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
159.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
160.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
161.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
162.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
163.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
164.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
165.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
166.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
167.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
168.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
169.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
170.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
171.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
172.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
173.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
174.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
175.	c.595G>A	p.A199T	missense	1	VUS	0.000000
176.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
177.	c.904C>A	p.L302M	missense	1	VUS	0.000000
178.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
179.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
180.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
181.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
182.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
183.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
184.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
185.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
186.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
187.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
188.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
189.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
190.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
191.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
192.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
193.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
194.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
195.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
196.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
197.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
198.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
199.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
200.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
201.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
202.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
203.	c.964T>A	p.S322T	missense	1	VUS	0.000000
204.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
205.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
206.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
207.	c.731T>G	p.F244C	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.