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