MYH7 protein-altering 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.2539A>G	p.K847E	missense	10	Likely Pathogenic	0.000000
6.	c.1063G>A	p.A355T	missense	10	Likely Pathogenic	0.000000
7.	c.1357C>T	p.R453C	missense	10	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.2207T>C	p.I736T	missense	6	Pathogenic	0.000000
14.	c.1207C>T	p.R403W	missense	6	Pathogenic	0.000000
15.	c.3158G>A	p.R1053Q	missense	6	Likely Pathogenic	0.000074
16.	c.1142C>A	p.A381D	missense	5	Likely Pathogenic	0.000000
17.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
18.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
19.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
20.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
21.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
22.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
23.	c.2167C>T	p.R723C	missense	4	Pathogenic	0.000024
24.	c.508G>A	p.E170K	missense	4	Pathogenic	0.000000
25.	c.3475G>A	p.V1159M	missense	4	VUS	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.958G>A	p.V320M	missense	4	VUS	0.000008
29.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
30.	c.611G>A	p.R204H	missense	3	VUS	0.000000
31.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
32.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
33.	c.715G>A	p.D239N	missense	3	Likely 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.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
37.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
38.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
39.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
40.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
41.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
42.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
43.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
44.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
45.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
46.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
47.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
48.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
49.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
50.	c.345C>A	p.Y115X	nonsense	2	VUS	0.000000
51.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
52.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
53.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
54.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
55.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
56.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
57.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
58.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
59.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
60.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
61.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
62.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
63.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
64.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
65.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
66.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
67.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
68.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
69.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
70.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
71.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
72.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
73.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
74.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
75.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
76.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
77.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
78.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
79.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
80.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
81.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
82.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
83.	c.500C>T	p.T167I	missense	1	VUS	0.000000
84.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
85.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
86.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
87.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
88.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
89.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
90.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
91.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
92.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
93.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
94.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
95.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
96.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
97.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
98.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
99.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
100.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
101.	c.4000C>T	p.Q1334X	nonsense	1	VUS	0.000000
102.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
103.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
104.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
105.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
106.	c.904C>A	p.L302M	missense	1	VUS	0.000000
107.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
108.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
109.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
110.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
111.	c.595G>A	p.A199T	missense	1	VUS	0.000000
112.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
113.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
114.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
115.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
116.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
117.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
118.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
119.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
120.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
121.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
122.	c.5110C>T	p.Q1704X	nonsense	1	VUS	0.000000
123.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
124.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
125.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
126.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
127.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
128.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
129.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
130.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
131.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
132.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
133.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
134.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
135.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
136.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
137.	c.964T>A	p.S322T	missense	1	VUS	0.000000
138.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
139.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
140.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
141.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
142.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
143.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
144.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
145.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
146.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
147.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
148.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
149.	c.809A>G	p.K270R	missense	1	VUS	0.000000
150.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
151.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
152.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
153.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
154.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
155.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
156.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
157.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
158.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
159.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
160.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
161.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
162.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
163.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
164.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
165.	c.793A>T	p.T265S	missense	1	VUS	0.000000
166.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
167.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
168.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
169.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
170.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
171.	c.677C>T	p.A226V	missense	1	VUS	0.000000
172.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
173.	c.2129C>A	p.P710H	missense	1	Likely Pathogenic	0.000000
174.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
175.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
176.	c.298G>A	p.A100T	missense	1	VUS	0.000016
177.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
178.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
179.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
180.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
181.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
182.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
183.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
184.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
185.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
186.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
187.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
188.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
189.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
190.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
191.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
192.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
193.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
194.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
195.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
196.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
197.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
198.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
199.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
200.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
201.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
202.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
203.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
204.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
205.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
206.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
207.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032

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.