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