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