MYH7 non-truncating variants in HCM cohorts

The table below lists the 434 rare (MAF<0.0001 in ExAC) non-truncating MYH7 variants identified in a cohort of 3200 HCM patients. When this rare variant frequency of 0.13562 is compared with a background population rate of 0.01350, there is a statistically significant case excess of 0.12212 (p<0.0001), which suggests that approximately 391 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.2221G>T	p.G741W	missense	8	Pathogenic	0.000000
9.	c.5135G>A	p.R1712Q	missense	8	VUS	0.000008
10.	c.2348G>A	p.R783H	missense	8	Likely Pathogenic	0.000016
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.3158G>A	p.R1053Q	missense	6	Likely Pathogenic	0.000074
14.	c.2207T>C	p.I736T	missense	6	Pathogenic	0.000000
15.	c.1207C>T	p.R403W	missense	6	Pathogenic	0.000000
16.	c.2722C>G	p.L908V	missense	5	Pathogenic	0.000000
17.	c.4066G>A	p.E1356K	missense	5	Likely Pathogenic	0.000000
18.	c.2770G>A	p.E924K	missense	5	Pathogenic	0.000000
19.	c.4130C>T	p.T1377M	missense	5	VUS	0.000000
20.	c.2155C>T	p.R719W	missense	5	Pathogenic	0.000000
21.	c.4135G>A	p.A1379T	missense	5	Pathogenic	0.000000
22.	c.1142C>A	p.A381D	missense	5	Likely 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.1208G>A	p.R403Q	missense	4	Pathogenic	0.000000
26.	c.343T>C	p.Y115H	missense	4	Likely Pathogenic	0.000008
27.	c.3475G>A	p.V1159M	missense	4	VUS	0.000000
28.	c.958G>A	p.V320M	missense	4	VUS	0.000008
29.	c.1370T>C	p.I457T	missense	3	Likely Pathogenic	0.000008
30.	c.2631G>C	p.M877I	missense	3	VUS	0.000000
31.	c.1279C>A	p.L427M	missense	3	Likely Pathogenic	0.000000
32.	c.2302G>A	p.G768R	missense	3	Likely Pathogenic	0.000000
33.	c.611G>A	p.R204H	missense	3	VUS	0.000000
34.	c.1063G>T	p.A355S	missense	3	VUS	0.000000
35.	c.715G>A	p.D239N	missense	3	Likely Pathogenic	0.000000
36.	c.2779G>A	p.E927K	missense	3	VUS	0.000000
37.	c.1856C>T	p.T619I	missense	3	VUS	0.000033
38.	c.746G>A	p.R249Q	missense	3	Pathogenic	0.000000
39.	c.5561C>T	p.T1854M	missense	2	VUS	0.000033
40.	c.427C>T	p.R143W	missense	2	Likely Pathogenic	0.000049
41.	c.1051A>G	p.K351E	missense	2	Likely Pathogenic	0.000000
42.	c.641G>A	p.G214D	missense	2	Likely Pathogenic	0.000000
43.	c.578A>G	p.Q193R	missense	2	Likely Pathogenic	0.000000
44.	c.1231G>A	p.V411I	missense	2	Likely Pathogenic	0.000008
45.	c.1182C>A	p.D394E	missense	2	VUS	0.000000
46.	c.1324C>T	p.R442C	missense	2	Likely Pathogenic	0.000008
47.	c.4259G>T	p.R1420L	missense	2	VUS	0.000000
48.	c.2359C>T	p.R787C	missense	2	Likely Pathogenic	0.000057
49.	c.1954A>G	p.R652G	missense	2	Likely Pathogenic	0.000008
50.	c.767G>A	p.G256E	missense	2	Likely Pathogenic	0.000000
51.	c.976G>C	p.A326P	missense	2	Likely Pathogenic	0.000067
52.	c.1268C>T	p.A423V	missense	2	VUS	0.000000
53.	c.4124A>G	p.Y1375C	missense	2	VUS	0.000000
54.	c.2572C>T	p.R858C	missense	2	VUS	0.000000
55.	c.2011C>T	p.R671C	missense	2	Likely Pathogenic	0.000000
56.	c.2536G>C	p.E846Q	missense	2	VUS	0.000000
57.	c.1405G>A	p.D469N	missense	2	VUS	0.000008
58.	c.1045A>G	p.M349V	missense	2	VUS	0.000024
59.	c.428G>A	p.R143Q	missense	2	Likely Pathogenic	0.000008
60.	c.5329G>A	p.A1777T	missense	2	VUS	0.000041
61.	c.1433T>A	p.I478N	missense	2	Likely Pathogenic	0.000000
62.	c.1447G>A	p.E483K	missense	2	Pathogenic	0.000008
63.	c.2220G>T	p.K740N	missense	2	Likely Pathogenic	0.000000
64.	c.1318G>A	p.V440M	missense	2	VUS	0.000000
65.	c.298G>A	p.A100T	missense	1	VUS	0.000016
66.	c.4132G>C	p.D1378H	missense	1	VUS	0.000000
67.	c.619A>C	p.K207Q	missense	1	Likely Pathogenic	0.000000
68.	c.5740G>A	p.E1914K	missense	1	VUS	0.000000
69.	c.4664A>G	p.E1555G	missense	1	VUS	0.000000
70.	c.788T>C	p.I263T	missense	1	Pathogenic	0.000000
71.	c.4030C>T	p.R1344W	missense	1	VUS	0.000016
72.	c.3289G>A	p.E1097K	missense	1	VUS	0.000000
73.	c.4258C>T	p.R1420W	missense	1	VUS	0.000008
74.	c.3548T>A	p.L1183Q	missense	1	VUS	0.000000
75.	c.2707G>C	p.E903Q	missense	1	VUS	0.000000
76.	c.4343A>G	p.N1448S	missense	1	VUS	0.000000
77.	c.1228T>G	p.Y410D	missense	1	Likely Pathogenic	0.000000
78.	c.3622G>A	p.D1208N	missense	1	VUS	0.000000
79.	c.2894A>G	p.E965G	missense	1	VUS	0.000000
80.	c.2788G>A	p.E930K	missense	1	Likely Pathogenic	0.000000
81.	c.1479G>A	p.M493I	missense	1	Likely Pathogenic	0.000000
82.	c.904C>A	p.L302M	missense	1	VUS	0.000000
83.	c.2606G>T	p.R869L	missense	1	VUS	0.000000
84.	c.2555T>C	p.M852T	missense	1	Likely Pathogenic	0.000000
85.	c.694A>C	p.N232H	missense	1	Likely Pathogenic	0.000000
86.	c.2680G>A	p.E894K	missense	1	VUS	0.000000
87.	c.964T>A	p.S322T	missense	1	VUS	0.000000
88.	c.5029C>T	p.R1677C	missense	1	VUS	0.000016
89.	c.2471T>C	p.V824A	missense	1	VUS	0.000000
90.	c.2156G>A	p.R719Q	missense	1	Pathogenic	0.000000
91.	c.1544T>C	p.M515T	missense	1	Pathogenic	0.000000
92.	c.983A>G	p.E328G	missense	1	Likely Pathogenic	0.000000
93.	c.1757T>C	p.V586A	missense	1	Likely Pathogenic	0.000000
94.	c.4787C>T	p.S1596L	missense	1	VUS	0.000041
95.	c.1208G>T	p.R403L	missense	1	Pathogenic	0.000000
96.	c.5172C>G	p.I1724M	missense	1	VUS	0.000000
97.	c.799C>G	p.L267V	missense	1	Likely Pathogenic	0.000000
98.	c.4276G>A	p.E1426K	missense	1	VUS	0.000000
99.	c.3803G>C	p.R1268P	missense	1	VUS	0.000000
100.	c.5647G>A	p.E1883K	missense	1	VUS	0.000000
101.	c.4532A>C	p.D1511A	missense	1	VUS	0.000000
102.	c.3341G>A	p.R1114H	missense	1	VUS	0.000000
103.	c.5471A>G	p.N1824S	missense	1	VUS	0.000000
104.	c.1753A>T	p.I585F	missense	1	VUS	0.000000
105.	c.3428T>G	p.L1143R	missense	1	VUS	0.000000
106.	c.5326A>G	p.S1776G	missense	1	Likely Pathogenic	0.000032
107.	c.3208G>A	p.E1070K	missense	1	VUS	0.000008
108.	c.3974C>T	p.A1325V	missense	1	VUS	0.000026
109.	c.3064A>G	p.K1022E	missense	1	VUS	0.000000
110.	c.80A>G	p.Q27R	missense	1	VUS	0.000000
111.	c.2776C>G	p.L926V	missense	1	VUS	0.000016
112.	c.1346C>T	p.T449I	missense	1	VUS	0.000000
113.	c.2573G>A	p.R858H	missense	1	Likely Pathogenic	0.000008
114.	c.731T>G	p.F244C	missense	1	Likely Pathogenic	0.000000
115.	c.3133C>T	p.R1045C	missense	1	Likely Pathogenic	0.000016
116.	c.2701G>C	p.A901P	missense	1	Likely Pathogenic	0.000000
117.	c.1121A>T	p.E374V	missense	1	Likely Pathogenic	0.000000
118.	c.2606G>A	p.R869H	missense	1	Likely Pathogenic	0.000032
119.	c.2069T>C	p.M690T	missense	1	Likely Pathogenic	0.000000
120.	c.2104A>G	p.I702V	missense	1	VUS	0.000000
121.	c.1436A>G	p.N479S	missense	1	Likely Pathogenic	0.000000
122.	c.4954G>T	p.D1652Y	missense	1	VUS	0.000024
123.	c.728G>A	p.R243H	missense	1	Likely Pathogenic	0.000008
124.	c.925G>A	p.D309N	missense	1	Likely Pathogenic	0.000024
125.	c.5773C>T	p.R1925C	missense	1	VUS	0.000000
126.	c.4108C>A	p.Q1370K	missense	1	VUS	0.000000
127.	c.5725C>T	p.R1909W	missense	1	VUS	0.000032
128.	c.4660G>A	p.E1554K	missense	1	VUS	0.000000
129.	c.3346G>A	p.E1116K	missense	1	VUS	0.000000
130.	c.2700T>A	p.D900E	missense	1	VUS	0.000000
131.	c.4004C>T	p.S1335L	missense	1	VUS	0.000033
132.	c.3229_3240del	p.Asp1077_Leu1080del	inframe	1	VUS	0.000000
133.	c.2273T>G	p.F758C	missense	1	Likely Pathogenic	0.000000
134.	c.4144C>T	p.R1382W	missense	1	VUS	0.000000
135.	c.3484G>A	p.E1162K	missense	1	VUS	0.000000
136.	c.5380C>A	p.Q1794K	missense	1	VUS	0.000000
137.	c.793A>T	p.T265S	missense	1	VUS	0.000000
138.	c.3138G>A	p.M1046I	missense	1	VUS	0.000024
139.	c.2501T>A	p.F834Y	missense	1	VUS	0.000000
140.	c.1207C>G	p.R403G	missense	1	Pathogenic	0.000000
141.	c.3578G>A	p.R1193H	missense	1	VUS	0.000000
142.	c.2785G>A	p.E929K	missense	1	Likely Pathogenic	0.000000
143.	c.1477A>T	p.M493L	missense	1	Likely Pathogenic	0.000000
144.	c.2549C>A	p.A850D	missense	1	Likely Pathogenic	0.000000
145.	c.677C>T	p.A226V	missense	1	VUS	0.000000
146.	c.2623_2625delGAG	p.Glu875del	inframe	1	Likely Pathogenic	0.000000
147.	c.920C>A	p.P307H	missense	1	Pathogenic	0.000000
148.	c.2738T>C	p.I913T	missense	1	VUS	0.000000
149.	c.2221G>A	p.G741R	missense	1	Pathogenic	0.000000
150.	c.5002A>G	p.K1668E	missense	1	VUS	0.000000
151.	c.1477A>G	p.M493V	missense	1	Likely Pathogenic	0.000000
152.	c.1358G>A	p.R453H	missense	1	Likely Pathogenic	0.000000
153.	c.1625A>G	p.K542R	missense	1	VUS	0.000000
154.	c.632C>T	p.P211L	missense	1	Likely Pathogenic	0.000024
155.	c.4919A>G	p.Q1640R	missense	1	VUS	0.000000
156.	c.789A>G	p.I263M	missense	1	Likely Pathogenic	0.000000
157.	c.5291T>A	p.M1764K	missense	1	VUS	0.000000
158.	c.4259G>A	p.R1420Q	missense	1	VUS	0.000000
159.	c.3593A>G	p.D1198G	missense	1	VUS	0.000000
160.	c.5587C>T	p.R1863W	missense	1	VUS	0.000008
161.	c.2881C>G	p.L961V	missense	1	VUS	0.000000
162.	c.4418A>G	p.E1473G	missense	1	VUS	0.000000
163.	c.4048G>A	p.E1350K	missense	1	VUS	0.000000
164.	c.3325A>G	p.K1109E	missense	1	VUS	0.000000
165.	c.3637G>A	p.V1213M	missense	1	VUS	0.000000
166.	c.2906A>C	p.H969P	missense	1	VUS	0.000000
167.	c.2791_2793delGAG		inframe	1	Likely Pathogenic	0.000000
168.	c.1579C>A	p.P527T	missense	1	VUS	0.000000
169.	c.3170G>A	p.G1057D	missense	1	VUS	0.000000
170.	c.2631G>A	p.M877I	missense	1	VUS	0.000000
171.	c.2389G>C	p.A797P	missense	1	Likely Pathogenic	0.000000
172.	c.2770G>C	p.E924Q	missense	1	VUS	0.000000
173.	c.1345A>T	p.T449S	missense	1	Likely Pathogenic	0.000000
174.	c.710G>A	p.R237Q	missense	1	VUS	0.000000
175.	c.3046A>G	p.K1016E	missense	1	VUS	0.000008
176.	c.2167C>G	p.R723G	missense	1	Pathogenic	0.000000
177.	c.2296A>C	p.K766Q	missense	1	Likely Pathogenic	0.000000
178.	c.5088G>C	p.E1696D	missense	1	VUS	0.000024
179.	c.1759G>A	p.D587N	missense	1	Likely Pathogenic	0.000000
180.	c.4817G>A	p.R1606H	missense	1	VUS	0.000049
181.	c.1216G>A	p.V406M	missense	1	Likely Pathogenic	0.000000
182.	c.2081G>A	p.R694H	missense	1	Likely Pathogenic	0.000000
183.	c.809A>G	p.K270R	missense	1	VUS	0.000000
184.	c.5704G>C	p.E1902Q	missense	1	VUS	0.000074
185.	c.4636G>C	p.E1546Q	missense	1	VUS	0.000000
186.	c.3373G>C	p.E1125Q	missense	1	VUS	0.000000
187.	c.5690G>A	p.R1897H	missense	1	VUS	0.000000
188.	c.3899A>T	p.Q1300L	missense	1	VUS	0.000000
189.	c.610C>T	p.R204C	missense	1	Likely Pathogenic	0.000024
190.	c.2683C>A	p.Q895K	missense	1	VUS	0.000000
191.	c.3231T>G	p.D1077E	missense	1	VUS	0.000000
192.	c.1804A>T	p.N602Y	missense	1	VUS	0.000000
193.	c.500C>T	p.T167I	missense	1	VUS	0.000000
194.	c.2602G>C	p.A868P	missense	1	VUS	0.000000
195.	c.737A>T	p.K246I	missense	1	Likely Pathogenic	0.000000
196.	c.3134G>T	p.R1045L	missense	1	VUS	0.000016
197.	c.2353A>G	p.I785V	missense	1	VUS	0.000000
198.	c.2711G>A	p.R904H	missense	1	VUS	0.000000
199.	c.3493A>G	p.K1165E	missense	1	VUS	0.000012
200.	c.2546T>C	p.M849T	missense	1	Likely Pathogenic	0.000000
201.	c.595G>A	p.A199T	missense	1	VUS	0.000000
202.	c.2183C>T	p.A728V	missense	1	VUS	0.000000
203.	c.4985G>A	p.R1662H	missense	1	VUS	0.000057
204.	c.2129C>A	p.P710H	missense	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.