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