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