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.1357C>T	p.R453C	missense	10	Pathogenic	0.000000
6.	c.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
7.	c.1063G>A	p.A355T	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.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.4130C>T	p.T1377M	missense	5	VUS	0.000000
17.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
18.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
19.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
20.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
21.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
22.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
23.	c.958G>A	p.V320M	missense	4	VUS	0.000008
24.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
25.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
26.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
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.2779G>A	p.E927K	missense	3	VUS	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.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
34.	c.2302G>A	p.G768R	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.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
39.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
40.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
41.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
42.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
43.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
44.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
45.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
46.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
47.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
48.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
49.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
50.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
51.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
52.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
53.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
54.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
55.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
56.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
57.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
58.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
59.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
60.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
61.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
62.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
63.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
64.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
65.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
66.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
67.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
68.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
69.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
70.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
71.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
72.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
73.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
74.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
75.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
76.	c.793A>T	p.T265S	missense	1	VUS	0.000000
77.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
78.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
79.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
80.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
81.	c.677C>T	p.A226V	missense	1	VUS	0.000000
82.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
83.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
84.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
85.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
86.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
87.	c.298G>A	p.A100T	missense	1	VUS	0.000016
88.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
89.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
90.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
91.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
92.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
93.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
94.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
95.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
96.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
97.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
98.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
99.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
100.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
101.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
102.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
103.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
104.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
105.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
106.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
107.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
108.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
109.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
110.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
111.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
112.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
113.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
114.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
115.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
116.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
117.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
118.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
119.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
120.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
121.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
122.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
123.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
124.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
125.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
126.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
127.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
128.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
129.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
130.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
131.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
132.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
133.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
134.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
135.	c.500C>T	p.T167I	missense	1	VUS	0.000000
136.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
137.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
138.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
139.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
140.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
141.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
142.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
143.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
144.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
145.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
146.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
147.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
148.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
149.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
150.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
151.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
152.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
153.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
154.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
155.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
156.	c.595G>A	p.A199T	missense	1	VUS	0.000000
157.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
158.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
159.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
160.	c.904C>A	p.L302M	missense	1	VUS	0.000000
161.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
162.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
163.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
164.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
165.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
166.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
167.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
168.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
169.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
170.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
171.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
172.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
173.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
174.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
175.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
176.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
177.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
178.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
179.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
180.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
181.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
182.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
183.	c.964T>A	p.S322T	missense	1	VUS	0.000000
184.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
185.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
186.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
187.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
188.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
189.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
190.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
191.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
192.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
193.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
194.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
195.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
196.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
197.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
198.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
199.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
200.	c.809A>G	p.K270R	missense	1	VUS	0.000000
201.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
202.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
203.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
204.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
205.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
206.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
207.	c.5690G>A	p.R1897H	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.