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