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

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.