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.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
2.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
3.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
4.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
5.	c.809A>G	p.K270R	missense	1	VUS	0.000000
6.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
7.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
8.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
9.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
10.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
11.	c.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
12.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
13.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
14.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
15.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
16.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
17.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
18.	c.1816G>A	p.V606M	missense	13	Pathogenic	0.000000
19.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
20.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
21.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
22.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
23.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
24.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
25.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
26.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
27.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
28.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
29.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
30.	c.793A>T	p.T265S	missense	1	VUS	0.000000
31.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
32.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
33.	c.677C>T	p.A226V	missense	1	VUS	0.000000
34.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
35.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
36.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
37.	c.958G>A	p.V320M	missense	4	VUS	0.000008
38.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
39.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
40.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
41.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
42.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
43.	c.2717A>G	p.D906G	missense	7	Likely Pathogenic	0.000000
44.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
45.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
46.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
47.	c.298G>A	p.A100T	missense	1	VUS	0.000016
48.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
49.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
50.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
51.	c.2207T>C	p.I736T	missense	6	Pathogenic	0.000000
52.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
53.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
54.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
55.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
56.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
57.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
58.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
59.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
60.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
61.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
62.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
63.	c.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
64.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
65.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
66.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
67.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
68.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
69.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
70.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
71.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
72.	c.5135G>A	p.R1712Q	missense	8	VUS	0.000008
73.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
74.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
75.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
76.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
77.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
78.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
79.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
80.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
81.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
82.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
83.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
84.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
85.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
86.	c.2681A>G	p.E894G	missense	7	Likely Pathogenic	0.000000
87.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
88.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
89.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
90.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
91.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
92.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
93.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
94.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
95.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
96.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
97.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
98.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
99.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
100.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
101.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
102.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
103.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
104.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
105.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
106.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
107.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
108.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
109.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
110.	c.500C>T	p.T167I	missense	1	VUS	0.000000
111.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
112.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
113.	c.1063G>A	p.A355T	missense	10	Likely Pathogenic	0.000000
114.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
115.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
116.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
117.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
118.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
119.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
120.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
121.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
122.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
123.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
124.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
125.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
126.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
127.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
128.	c.611G>A	p.R204H	missense	3	VUS	0.000000
129.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
130.	c.2609G>A	p.R870H	missense	13	Pathogenic	0.000000
131.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
132.	c.2348G>A	p.R783H	missense	8	Likely Pathogenic	0.000016
133.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
134.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
135.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
136.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
137.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
138.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
139.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
140.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
141.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
142.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
143.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
144.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
145.	c.595G>A	p.A199T	missense	1	VUS	0.000000
146.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
147.	c.1207C>T	p.R403W	missense	6	Pathogenic	0.000000
148.	c.904C>A	p.L302M	missense	1	VUS	0.000000
149.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
150.	c.1357C>T	p.R453C	missense	10	Pathogenic	0.000000
151.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
152.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
153.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
154.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
155.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
156.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
157.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
158.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
159.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
160.	c.3158G>A	p.R1053Q	missense	6	Likely Pathogenic	0.000074
161.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
162.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
163.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
164.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
165.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
166.	c.2389G>A	p.A797T	missense	24	Pathogenic	0.000032
167.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
168.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
169.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
170.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
171.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
172.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
173.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
174.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
175.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
176.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
177.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
178.	c.2221G>T	p.G741W	missense	8	Pathogenic	0.000000
179.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
180.	c.1988G>A	p.R663H	missense	17	Pathogenic	0.000016
181.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
182.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
183.	c.964T>A	p.S322T	missense	1	VUS	0.000000
184.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
185.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
186.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
187.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
188.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
189.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
190.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
191.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
192.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
193.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
194.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
195.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
196.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
197.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
198.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
199.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
200.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
201.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
202.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
203.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
204.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
205.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
206.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
207.	c.2791_2793delGAG		inframe	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.