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