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.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.2681A>G	p.E894G	missense	7	Likely Pathogenic	0.000000
12.	c.2717A>G	p.D906G	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.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
17.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
18.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
19.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
20.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
21.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
22.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
23.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
24.	c.958G>A	p.V320M	missense	4	VUS	0.000008
25.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
26.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
27.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
28.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
29.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
30.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
31.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
32.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
33.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
34.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
35.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
36.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
37.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
38.	c.611G>A	p.R204H	missense	3	VUS	0.000000
39.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
40.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
41.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
42.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
43.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
44.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
45.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
46.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
47.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
48.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
49.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
50.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
51.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
52.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
53.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
54.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
55.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
56.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
57.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
58.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
59.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
60.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
61.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
62.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
63.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
64.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
65.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
66.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
67.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
68.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
69.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
70.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
71.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
72.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
73.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
74.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
75.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
76.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
77.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
78.	c.964T>A	p.S322T	missense	1	VUS	0.000000
79.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
80.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
81.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
82.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
83.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
84.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
85.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
86.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
87.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
88.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
89.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
90.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
91.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
92.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
93.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
94.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
95.	c.809A>G	p.K270R	missense	1	VUS	0.000000
96.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
97.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
98.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
99.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
100.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
101.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
102.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
103.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
104.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
105.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
106.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
107.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
108.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
109.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
110.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
111.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
112.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
113.	c.793A>T	p.T265S	missense	1	VUS	0.000000
114.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
115.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
116.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
117.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
118.	c.677C>T	p.A226V	missense	1	VUS	0.000000
119.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
120.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
121.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
122.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
123.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
124.	c.298G>A	p.A100T	missense	1	VUS	0.000016
125.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
126.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
127.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
128.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
129.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
130.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
131.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
132.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
133.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
134.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
135.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
136.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
137.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
138.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
139.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
140.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
141.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
142.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
143.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
144.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
145.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
146.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
147.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
148.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
149.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
150.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
151.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
152.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
153.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
154.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
155.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
156.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
157.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
158.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
159.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
160.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
161.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
162.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
163.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
164.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
165.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
166.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
167.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
168.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
169.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
170.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
171.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
172.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
173.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
174.	c.500C>T	p.T167I	missense	1	VUS	0.000000
175.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
176.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
177.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
178.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
179.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
180.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
181.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
182.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
183.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
184.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
185.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
186.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
187.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
188.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
189.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
190.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
191.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
192.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
193.	c.595G>A	p.A199T	missense	1	VUS	0.000000
194.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
195.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
196.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
197.	c.904C>A	p.L302M	missense	1	VUS	0.000000
198.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
199.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
200.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
201.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
202.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
203.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
204.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
205.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
206.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
207.	c.1358G>A	p.R453H	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.