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