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