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