MYBPC3 non-truncating variants in HCM cohorts

The table below lists the 272 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.09341 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.07457 (p<0.0001), which suggests that approximately 218 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 (2912)▼	LMM class	ExAC frequency
1.	c.1504C>T	p.R502W	missense	45	Pathogenic	0.000024
2.	c.772G>A	p.E258K	missense	21	Pathogenic	0.000039
3.	c.1624G>C	p.E542Q	missense	17	Likely Pathogenic	0.000024
4.	c.1484G>A	p.R495Q	missense	10	VUS favour pathogenic	0.000008
5.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
6.	c.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
7.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
8.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
9.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
10.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
11.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
12.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
13.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
14.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
15.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
16.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
17.	c.355G>A	p.E119K	missense	3	VUS	0.000000
18.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
19.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
20.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
21.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
22.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
23.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
24.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
25.	c.814C>T	p.R272C	missense	2	VUS	0.000083
26.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
27.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
28.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
29.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
30.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
31.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
32.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
33.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
34.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
35.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
36.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
37.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
38.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
39.	c.853G>A	p.D285N	missense	1	VUS	0.000000
40.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
41.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
42.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
43.	c.932C>T	p.S311L	missense	1	VUS	0.000000
44.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
45.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
46.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
47.	c.451G>A	p.D151N	missense	1	VUS	0.000041
48.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
49.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
50.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
51.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
52.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
53.	c.713G>A	p.R238H	missense	1	VUS	0.000074
54.	c.566T>A	p.V189D	missense	1	VUS	0.000000
55.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
56.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
57.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
58.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
59.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
60.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
61.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
62.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
63.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
64.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
65.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
66.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
67.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
68.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
69.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
70.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
71.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
72.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
73.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
74.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
75.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
76.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
77.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
78.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
79.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
80.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
81.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
82.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
83.	c.436A>C	p.T146P	missense	1	VUS	0.000000
84.	c.326C>T	p.A109V	missense	1	VUS	0.000000
85.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
86.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
87.	c.103C>T	p.R35W	missense	1	VUS	0.000056
88.	c.931T>A	p.S311T	missense	1	VUS	0.000000
89.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
90.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
91.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
92.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
93.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
94.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
95.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
96.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
97.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
98.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
99.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
100.	c.518C>A	p.T173N	missense	1	VUS	0.000000
101.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
102.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
103.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
104.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
105.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
106.	c.373G>T	p.A125S	missense	1	VUS	0.000000
107.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
108.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
109.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
110.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
111.	c.1586C>G	p.T529S	missense	1	VUS favour 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.