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