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