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