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.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.2207T>C	p.I736T	missense	6	Pathogenic	0.000000
14.	c.3158G>A	p.R1053Q	missense	6	Likely Pathogenic	0.000074
15.	c.1207C>T	p.R403W	missense	6	Pathogenic	0.000000
16.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
17.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
18.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
19.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
20.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
21.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
22.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
23.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
24.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
25.	c.958G>A	p.V320M	missense	4	VUS	0.000008
26.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
27.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
28.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
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.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
33.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
34.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
35.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
36.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
37.	c.611G>A	p.R204H	missense	3	VUS	0.000000
38.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
39.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
40.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
41.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
42.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
43.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
44.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
45.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
46.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
47.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
48.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
49.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
50.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
51.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
52.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
53.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
54.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
55.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
56.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
57.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
58.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
59.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
60.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
61.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
62.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
63.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
64.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
65.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
66.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
67.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
68.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
69.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
70.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
71.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
72.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
73.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
74.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
75.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
76.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
77.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
78.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
79.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
80.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
81.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
82.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
83.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
84.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
85.	c.964T>A	p.S322T	missense	1	VUS	0.000000
86.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
87.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
88.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
89.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
90.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
91.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
92.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
93.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
94.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
95.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
96.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
97.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
98.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
99.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
100.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
101.	c.809A>G	p.K270R	missense	1	VUS	0.000000
102.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
103.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
104.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
105.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
106.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
107.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
108.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
109.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
110.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
111.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
112.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
113.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
114.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
115.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
116.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
117.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
118.	c.793A>T	p.T265S	missense	1	VUS	0.000000
119.	c.677C>T	p.A226V	missense	1	VUS	0.000000
120.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
121.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
122.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
123.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
124.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
125.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
126.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
127.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
128.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
129.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
130.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
131.	c.298G>A	p.A100T	missense	1	VUS	0.000016
132.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
133.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
134.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
135.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
136.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
137.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
138.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
139.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
140.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
141.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
142.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
143.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
144.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
145.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
146.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
147.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
148.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
149.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
150.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
151.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
152.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
153.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
154.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
155.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
156.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
157.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
158.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
159.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
160.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
161.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
162.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
163.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
164.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
165.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
166.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
167.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
168.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
169.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
170.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
171.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
172.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
173.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
174.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
175.	c.500C>T	p.T167I	missense	1	VUS	0.000000
176.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
177.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
178.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
179.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
180.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
181.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
182.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
183.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
184.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
185.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
186.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
187.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
188.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
189.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
190.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
191.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
192.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
193.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
194.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
195.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
196.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
197.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
198.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
199.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
200.	c.595G>A	p.A199T	missense	1	VUS	0.000000
201.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
202.	c.904C>A	p.L302M	missense	1	VUS	0.000000
203.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
204.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
205.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
206.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
207.	c.694A>C	p.N232H	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.