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