MYBPC3 non-truncating variants in HCM cohorts

The table below lists the 338 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.10346 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.08462 (p<0.0001), which suggests that approximately 277 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 (3267)▼	OMGL class	ExAC frequency
1.	c.1504C>T	p.R502W	missense	59	Pathogenic	0.000024
2.	c.772G>A	p.E258K	missense	47	Pathogenic	0.000039
3.	c.1624G>C	p.E542Q	missense	24	Pathogenic	0.000024
4.	c.655G>C	p.V219L	missense	18	Likely Pathogenic	0.000000
5.	c.2429G>A	p.R810H	missense	11	VUS	0.000033
6.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
7.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
8.	c.3771C>A	p.N1257K	missense	9	Likely Pathogenic	0.000000
9.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
10.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
11.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
12.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
13.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
14.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
15.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
16.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
17.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
18.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
19.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
20.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
21.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
22.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
23.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
24.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
25.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
26.	c.557C>T	p.P186L	missense	2	VUS	0.000047
27.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
28.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
29.	c.818G>A	p.R273H	missense	2	VUS	0.000042
30.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
31.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
32.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
33.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
34.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
35.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
36.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
37.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
38.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
39.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
40.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
41.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
42.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
43.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
44.	c.49C>T	p.R17W	missense	1	VUS	0.000023
45.	c.994G>A	p.E332K	missense	1	VUS	0.000009
46.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
47.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
48.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
49.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
50.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
51.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
52.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
53.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
54.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
55.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
56.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
57.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
58.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
59.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
60.	c.631G>A	p.D211N	missense	1	VUS	0.000009
61.	c.187C>T	p.R63W	missense	1	VUS	0.000077
62.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
63.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
64.	c.241G>T	p.V81F	missense	1	VUS	0.000000
65.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
66.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
67.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
68.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
69.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
70.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
71.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
72.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
73.	c.373G>T	p.A125S	missense	1	VUS	0.000000
74.	c.365C>A	p.A122D	missense	1	VUS	0.000000
75.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
76.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
77.	c.148A>G	p.S50G	missense	1	VUS	0.000038
78.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
79.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
80.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
81.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
82.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
83.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
84.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
85.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
86.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
87.	c.532G>A	p.V178M	missense	1	VUS	0.000020
88.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
89.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
90.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
91.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
92.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
93.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
94.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
95.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
96.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
97.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
98.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
99.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
100.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
101.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
102.	c.799C>G	p.L267V	missense	1	VUS	0.000080
103.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
104.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
105.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
106.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
107.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
108.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
109.	c.1455A>T	p.K485N	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.