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