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.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
6.	c.1357C>T	p.R453C	missense	10	Pathogenic	0.000000
7.	c.1063G>A	p.A355T	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.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.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
17.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
18.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
19.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
20.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
21.	c.2155C>T	p.R719W	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.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
25.	c.958G>A	p.V320M	missense	4	VUS	0.000008
26.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
27.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
28.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
29.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
30.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
31.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
32.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
33.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
34.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
35.	c.611G>A	p.R204H	missense	3	VUS	0.000000
36.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
37.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
38.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
39.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
40.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
41.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
42.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
43.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
44.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
45.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
46.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
47.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
48.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
49.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
50.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
51.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
52.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
53.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
54.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
55.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
56.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
57.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
58.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
59.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
60.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
61.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
62.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
63.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
64.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
65.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
66.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
67.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
68.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
69.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
70.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
71.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
72.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
73.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
74.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
75.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
76.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
77.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
78.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
79.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
80.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
81.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
82.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
83.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
84.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
85.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
86.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
87.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
88.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
89.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
90.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
91.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
92.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
93.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
94.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
95.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
96.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
97.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
98.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
99.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
100.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
101.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
102.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
103.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
104.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
105.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
106.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
107.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
108.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
109.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
110.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
111.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
112.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
113.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
114.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
115.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
116.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
117.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
118.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
119.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
120.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
121.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
122.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
123.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
124.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
125.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
126.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
127.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
128.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
129.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
130.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
131.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
132.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
133.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
134.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
135.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
136.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
137.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
138.	c.809A>G	p.K270R	missense	1	VUS	0.000000
139.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
140.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
141.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
142.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
143.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
144.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
145.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
146.	c.298G>A	p.A100T	missense	1	VUS	0.000016
147.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
148.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
149.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
150.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
151.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
152.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
153.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
154.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
155.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
156.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
157.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
158.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
159.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
160.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
161.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
162.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
163.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
164.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
165.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
166.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
167.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
168.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
169.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
170.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
171.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
172.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
173.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
174.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
175.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
176.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
177.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
178.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
179.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
180.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
181.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
182.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
183.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
184.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
185.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
186.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
187.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
188.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
189.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
190.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
191.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
192.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
193.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
194.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
195.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
196.	c.964T>A	p.S322T	missense	1	VUS	0.000000
197.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
198.	c.904C>A	p.L302M	missense	1	VUS	0.000000
199.	c.793A>T	p.T265S	missense	1	VUS	0.000000
200.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
201.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
202.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
203.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
204.	c.677C>T	p.A226V	missense	1	VUS	0.000000
205.	c.595G>A	p.A199T	missense	1	VUS	0.000000
206.	c.500C>T	p.T167I	missense	1	VUS	0.000000
207.	c.80A>G	p.Q27R	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.