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