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