Disease: CM
| Position | Domain | Domain position | SNV | RS | Source | Comments | MAF | Zygosity | Structural Position | AlphaMissense (IC) | REVEL | Rhapsody | DUET | PolyPhen-2 | Condel | Q(SASA) |
Site annotation |
mCSM PPI |
Predicted PPI site |
AFR | AMR | EAS | EUR | FIN | NFE | SAS |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
54  |
Ig-1 |
49 | V/M | rs139517732  |
gnomAD-2.1.1 | None | 0.0000425 | None | 121 |
0.2615 | 0.39 | 0.517 | -0.932 | 0.662 | None | 0.1304 | None | -1.137(TCAP) | N | 0 | 2.82E-05 | 5.52597E-04 | None | 0 | 0 | 0 | 54 |
Ig-1 |
49 | V/M | rs139517732 |
gnomAD-3.1.2 | None | 0.0000394 | None | 121 |
0.2615 | 0.39 | 0.517 | -0.932 | 0.662 | None | 0.1304 | None | -1.137(TCAP) | N | 0 | 6.54E-05 | 9.63391E-04 | None | 0 | 0 | 0 | 54 |
Ig-1 |
49 | V/M | rs139517732 |
1000 genomes | None | 0.000599042 | None | 121 |
0.2615 | 0.39 | 0.517 | -0.932 | 0.662 | None | 0.1304 | None | -1.137(TCAP) | N | 0 | 0 | 3E-03 | 0 | None | None | 0 | 54 |
Ig-1 |
49 | V/M | rs139517732 |
Itoh-Satoh (2002)
Kumar (2016)
| Genetic analysis of JP DCM families, unknown penetrance; decreases binding of TTN to TCAP (Y2H assay); Variant prioritisation; filtering with pathogenicity/stability tools; MD analysis of binding of TTN to TCAP | None | het | 121 |
0.2615 | 0.39 | 0.517 | -0.932 | 0.662 | None | 0.1304 | None | -1.137(TCAP) | N | None | None | None | None | None | None | None | 54 |
Ig-1 |
49 | V/M | rs139517732 |
gnomAD-4.0.0 | None | 0.0000371722 | None | 121 |
0.2615 | 0.39 | 0.517 | -0.932 | 0.662 | None | 0.1304 | None | -1.137(TCAP) | N | 1.33284E-05 | 3.33178E-05 | 1.11458E-03 | None | 0 | 3.38981E-06 | 0 | 178 |
Ig-2 |
75 | A/D | None |
Hastings (2016)
Jiang (2021)
| Linkage analysis in single 3-generation DCM family, co-segregates with condition (n = 8, 8 affected (14 total)); features of LVNC; domain destabilisation and impaired TCAP binding in vitro; knock-in mice mutant show phenotype under challenge conditions | None | het | 158 |
0.9987 | 0.833 | 0.571 | -3.04 | 0.993 | None | 0.0809 | None | -1.921(TCAP) | N | None | None | None | None | None | None | None | 740 |
None | None | R/L | rs28933405 |
Satoh (1999)
| Increases binding of TTN to ACTN1 (Y2H assay) | None | het | None |
0.141 | 0.319 | None | None | None | None | None | None | None | None | None | None | None | None | None | None | None | 740 |
None | None | R/L | rs28933405 |
gnomAD-4.0.0 | None | 0.000000684078 | None | None |
0.141 | 0.319 | None | None | None | None | None | None | None | None | 0 | 0 | 0 | None | 0 | 8.99298E-07 | 0 | 743 |
None | None | A/V | rs267607157 |
gnomAD-3.1.2 | None | 0.0000131 | None | None |
0.1042 | 0.273 | None | None | None | None | None | None | None | None | 0 | 0 | 3.84911E-04 | None | 0 | 0 | 0 | 743 |
None | None | A/V | rs267607157 |
Itoh-Satoh (2002)
| Genetic analysis of JP DCM families, unknown penetrance; decreases binding of TTN to ACTN1 (Y2H assay) | None | het | None |
0.1042 | 0.273 | None | None | None | None | None | None | None | None | None | None | None | None | None | None | None | 743 |
None | None | A/V | rs267607157 |
gnomAD-4.0.0 | None | 0.000015368 | None | None |
0.1042 | 0.273 | None | None | None | None | None | None | None | None | 0 | 0 | 2.90909E-04 | None | 0 | 0 | 0 | 976 |
Ig-3 |
34 | W/R | rs267607155 |
Gerull (2002)
Herman (2012)
| Linkage analysis in single DCM family, incomplete penetrance (n = 15, 11 affected, 4 unaffected carriers (total 35)) | None | het / comp het with R21201* | 48 |
0.9999 | 0.96 | 0.824 | -2.071 | 1.0 | None | 0.1431 | None | None | N | None | None | None | None | None | None | None | 4116 |
None | None | S/Y | None |
Itoh-Satoh (2002)
Matsumoto (2006)
| Increases binding of TTN to FHL2 (Y2H assay) | None | het | None |
0.0933 | 0.237 | None | None | None | None | None | None | None | None | None | None | None | None | None | None | None | 4116 |
None | None | S/Y | None | gnomAD-4.0.0 | None | 0.00000615763 | None | None |
0.0933 | 0.237 | None | None | None | None | None | None | None | None | 0 | 0 | 0 | None | 0 | 8.09492E-06 | 0 | 4714 |
Ig-30 |
15 | G/D | rs750125429 |
gnomAD-2.1.1 | None | 0.0000823 | None | 24 |
0.8677 | 0.814 | 0.791 | -0.914 | 0.997 | None | 0.3238 | None | None | I | 0 | 0 | 1.08348E-03 | None | 0 | 0 | 1.56E-05 | 4714 |
Ig-30 |
15 | G/D | rs750125429 |
gnomAD-3.1.2 | None | 0.0000329 | None | 24 |
0.8677 | 0.814 | 0.791 | -0.914 | 0.997 | None | 0.3238 | None | None | I | 0 | 0 | 9.61908E-04 | None | 0 | 0 | 0 | 4714 |
Ig-30 |
15 | G/D | rs750125429 |
Liu (2008)
| Genetic analysis of CN DCM families (n = 2, 2 affected) | None | het | 24 |
0.8677 | 0.814 | 0.791 | -0.914 | 0.997 | None | 0.3238 | None | None | I | None | None | None | None | None | None | None | 4714 |
Ig-30 |
15 | G/D | rs750125429 |
gnomAD-4.0.0 | None | 0.0000235542 | None | 24 |
0.8677 | 0.814 | 0.791 | -0.914 | 0.997 | None | 0.3238 | None | None | I | 0 | 0 | 6.92242E-04 | None | 0 | 5.0863E-06 | 0 | 4780 |
Ig-30 |
81 | S/N | rs147879266 |
gnomAD-2.1.1 | None | 0.0000893 | None | 165 |
0.258 | 0.207 | 0.452 | 0.027 | 0.979 | None | 0.3911 | None | None | I | 0 | 0 | 1.02627E-03 | None | 1.30787E-04 | 0 | 7.82E-06 | 4780 |
Ig-30 |
81 | S/N | rs147879266 |
gnomAD-3.1.2 | None | 0.0000526 | None | 165 |
0.258 | 0.207 | 0.452 | 0.027 | 0.979 | None | 0.3911 | None | None | I | 0 | 0 | 7.70713E-04 | None | 0 | 1.47E-05 | 6.21633E-04 | 4780 |
Ig-30 |
81 | S/N | rs147879266 |
1000 genomes | None | 0.000199681 | None | 165 |
0.258 | 0.207 | 0.452 | 0.027 | 0.979 | None | 0.3911 | None | None | I | 0 | 0 | 1E-03 | 0 | None | None | 0 | 4780 |
Ig-30 |
81 | S/N | rs147879266 |
Itoh-Satoh (2002)
| Genetic analysis of JP DCM families | None | het | 165 |
0.258 | 0.207 | 0.452 | 0.027 | 0.979 | None | 0.3911 | None | None | I | None | None | None | None | None | None | None | 4780 |
Ig-30 |
81 | S/N | rs147879266 |
gnomAD-4.0.0 | None | 0.0000439978 | None | 165 |
0.258 | 0.207 | 0.452 | 0.027 | 0.979 | None | 0.3911 | None | None | I | 0 | 0 | 1.04794E-03 | None | 0 | 3.39068E-06 | 1.64712E-04 | 4854 |
Ig-31 |
60 | L/F | rs1196213888 |
gnomAD-2.1.1 | None | 0.00000402 | None | 140 |
0.1717 | 0.489 | 0.731 | -1.755 | 0.942 | None | 0.0802 | None | None | N | 0 | 2.9E-05 | 0 | None | 0 | 0 | 0 | 4854 |
Ig-31 |
60 | L/F | rs1196213888 |
gnomAD-3.1.2 | None | 0.0000263 | None | 140 |
0.1717 | 0.489 | 0.731 | -1.755 | 0.942 | None | 0.0802 | None | None | N | 2.41E-05 | 1.30959E-04 | 0 | None | 0 | 0 | 0 | 4854 |
Ig-31 |
60 | L/F | rs1196213888 |
Roncarati (2013)
| WES prioritisation in single DCM family; co-segregates with severe phenotype when inherited alongside LMNA variant K219T (n = 5, 5 severe phenotype (total 16)) | None | het; co-inherited with LMNA mutant p.K219T | 140 |
0.1717 | 0.489 | 0.731 | -1.755 | 0.942 | None | 0.0802 | None | None | N | None | None | None | None | None | None | None | 4854 |
Ig-31 |
60 | L/F | rs1196213888 |
gnomAD-4.0.0 | None | 0.00000768582 | None | 140 |
0.1717 | 0.489 | 0.731 | -1.755 | 0.942 | None | 0.0802 | None | None | N | 1.69107E-05 | 5.08423E-05 | 0 | None | 0 | 0 | 1.34005E-05 | 9744 |
Ig-83 |
47 | R/H | rs760305440 |
gnomAD-2.1.1 | None | 0.0000178 | None | 115 |
0.7704 | 0.502 | 0.675 | -1.388 | 1.0 | None | 0.3344 | None | None | N | 4.14E-05 | 0 | 0 | None | 0 | 0 | 3.12E-05 | 9744 |
Ig-83 |
47 | R/H | rs760305440 |
gnomAD-3.1.2 | None | 0.0000526 | None | 115 |
0.7704 | 0.502 | 0.675 | -1.388 | 1.0 | None | 0.3344 | None | None | N | 4.83E-05 | 1.30993E-04 | 0 | None | 0 | 5.88E-05 | 0 | 9744 |
Ig-83 |
47 | R/H | rs760305440 |
Arimura (2009)
Lopes (2013)
| Increases binding of TTN to CARP (Co-IP assay); alters subcellular localisation of CARP (Myc-tag) | None | het | 115 |
0.7704 | 0.502 | 0.675 | -1.388 | 1.0 | None | 0.3344 | None | None | N | None | None | None | None | None | None | None | 9744 |
Ig-83 |
47 | R/H | rs760305440 |
gnomAD-4.0.0 | None | 0.0000526723 | None | 115 |
0.7704 | 0.502 | 0.675 | -1.388 | 1.0 | None | 0.3344 | None | None | N | 2.67044E-05 | 5.00067E-05 | 2.22787E-05 | None | 0 | 6.10253E-05 | 2.19573E-05 | 9848 |
None | None | R/Q | rs773444238 |
gnomAD-2.1.1 | None | 0.0000121 | None | None |
0.9093 | 0.85 | None | None | None | None | None | None | None | None | 0 | 0 | 1.11284E-04 | None | 3.27E-05 | 0 | 0 | 9848 |
None | None | R/Q | rs773444238 |
gnomAD-3.1.2 | None | 0.00000657 | None | None |
0.9093 | 0.85 | None | None | None | None | None | None | None | None | 0 | 0 | 1.92308E-04 | None | 0 | 0 | 0 | 9848 |
None | None | R/Q | rs773444238 |
Arimura (2009)
| Increases binding of TTN to CARP (Co-IP assay); alters subcellular localisation of CARP (Myc-tag); co-segregation within family (n = 2, 2 affected (total 3)) | None | het | None |
0.9093 | 0.85 | None | None | None | None | None | None | None | None | None | None | None | None | None | None | None | 9848 |
None | None | R/Q | rs773444238 |
gnomAD-4.0.0 | None | 0.0000179725 | None | None |
0.9093 | 0.85 | None | None | None | None | None | None | None | None | 0 | 0 | 2.00597E-04 | None | 0 | 1.27147E-05 | 3.29533E-05 | 13702 |
Ig-87 |
19 | S/P | rs72650078 |
gnomAD-3.1.2 | None | 0.00000658 | None | 25 |
0.5141 | 0.463 | 0.647 | -0.375 | 0.999 | None | 0.1938 | None | None | N | 0 | 0 | 0 | None | 0 | 1.47E-05 | 0 | 13702 |
Ig-87 |
19 | S/P | rs72650078 |
Begay (2015)
Zuo (2021)
| WGS prioritisation; filtering with ANNOVAR; co-segregates within 2-generation family (n = 2, 2 affected (total 3)); moderate destabilisation of domain (SM-AFM) | None | het | 25 |
0.5141 | 0.463 | 0.647 | -0.375 | 0.999 | None | 0.1938 | None | None | N | None | None | None | None | None | None | None | 13702 |
Ig-87 |
19 | S/P | rs72650078 |
gnomAD-4.0.0 | None | 0.00000640861 | None | 25 |
0.5141 | 0.463 | 0.647 | -0.375 | 0.999 | None | 0.1938 | None | None | N | 0 | 0 | 0 | None | 0 | 1.19705E-05 | 0 | 14640 |
Ig-97 |
55 | R/C | rs72650088 |
gnomAD-2.1.1 | None | 0.0000282 | None | 136 |
0.313 | 0.296 | 0.867 | -1.68 | 1.0 | None | 0.124 | None | None | N | 0 | 0 | 0 | None | 0 | 0 | 6.23E-05 | 14640 |
Ig-97 |
55 | R/C | rs72650088 |
gnomAD-3.1.2 | None | 0.0000197 | None | 136 |
0.313 | 0.296 | 0.867 | -1.68 | 1.0 | None | 0.124 | None | None | N | 0 | 0 | 0 | None | 0 | 4.41E-05 | 0 | 14640 |
Ig-97 |
55 | R/C | rs72650088 |
Begay (2015)
Zuo (2021)
| WGS prioritisation; filtering with ANNOVAR; co-segregates within 2-generation family (n = 2, 2 affected (3 total)); significant destabilisation of domain (SM-AFM) | None | comp het with E29590Q | 136 |
0.313 | 0.296 | 0.867 | -1.68 | 1.0 | None | 0.124 | None | None | N | None | None | None | None | None | None | None | 14640 |
Ig-97 |
55 | R/C | rs72650088 |
gnomAD-4.0.0 | None | 0.0000216969 | None | 136 |
0.313 | 0.296 | 0.867 | -1.68 | 1.0 | None | 0.124 | None | None | N | 0 | 0 | 2.23604E-05 | None | 0 | 2.7128E-05 | 1.0981E-05 | 16686 |
Fn3-9 |
36 | Y/C | rs2056512518 |
Peled (2013)
| Segregation analysis in single RCM family, co-segregates with phenotype (n = 5, 5 affected (total 13)) | None | het | 38 |
0.9745 | 0.962 | 0.887 | -2.208 | 1.0 | None | 0.1035 | None | None | N | None | None | None | None | None | None | None | 28118 |
Fn3-92 |
64 | R/H | rs72648220 |
gnomAD-2.1.1 | None | 0.0000363 | None | 96 |
0.0963 | 0.299 | 0.585 | -0.514 | 1.0 | None | 0.8932 | None | None | I | 0 | 8.71E-05 | 5.6E-05 | None | 0 | 0 | 4.46E-05 | 28118 |
Fn3-92 |
64 | R/H | rs72648220 |
gnomAD-3.1.2 | None | 0.0000526 | None | 96 |
0.0963 | 0.299 | 0.585 | -0.514 | 1.0 | None | 0.8932 | None | None | I | 7.24E-05 | 1.3101E-04 | 0 | None | 0 | 4.41E-05 | 0 | 28118 |
Fn3-92 |
64 | R/H | rs72648220 |
1000 genomes | None | 0.000199681 | None | 96 |
0.0963 | 0.299 | 0.585 | -0.514 | 1.0 | None | 0.8932 | None | None | I | 0 | 1.4E-03 | 0 | 0 | None | None | 0 | 28118 |
Fn3-92 |
64 | R/H | rs72648220 |
Begay (2015)
| WGS prioritisation; filtering with ANNOVAR; co-segregates within family (n = 2, 2 affected (total 2)) | None | het | 96 |
0.0963 | 0.299 | 0.585 | -0.514 | 1.0 | None | 0.8932 | None | None | I | None | None | None | None | None | None | None | 28118 |
Fn3-92 |
64 | R/H | rs72648220 |
gnomAD-4.0.0 | None | 0.0000185924 | None | 96 |
0.0963 | 0.299 | 0.585 | -0.514 | 1.0 | None | 0.8932 | None | None | I | 5.33248E-05 | 1.0001E-04 | 0 | None | 0 | 1.61057E-05 | 0 | 29303 |
Fn3-101 |
67 | S/G | rs72648231 |
gnomAD-3.1.2 | None | 0.00000657 | None | 98 |
0.1133 | 0.189 | 0.391 | -0.938 | 0.948 | None | 0.3595 | None | None | N | 0 | 0 | 0 | None | 0 | 1.47E-05 | 0 | 29303 |
Fn3-101 |
67 | S/G | rs72648231 |
Begay (2015)
| WGS prioritisation; filtering with ANNOVAR; co-segregates within 2-generation family (n = 2, 2 affected (total 2)); LMNA variant also observed | None | het; co-inherited with LMNA mutant c.936G>A | 98 |
0.1133 | 0.189 | 0.391 | -0.938 | 0.948 | None | 0.3595 | None | None | N | None | None | None | None | None | None | None | 29303 |
Fn3-101 |
67 | S/G | rs72648231 |
gnomAD-4.0.0 | None | 0.00000768472 | None | 98 |
0.1133 | 0.189 | 0.391 | -0.938 | 0.948 | None | 0.3595 | None | None | N | 0 | 0 | 0 | None | 0 | 1.4355E-05 | 0 | 29590 |
Fn3-103 |
58 | E/Q | rs72648236 |
gnomAD-2.1.1 | None | 0.00000402 | None | 88 |
0.1587 | 0.256 | 0.401 | -0.202 | 0.891 | None | 0.563 | None | None | N | 0 | 0 | 0 | None | 0 | 0 | 8.88E-06 | 29590 |
Fn3-103 |
58 | E/Q | rs72648236 |
Begay (2015)
| WGS prioritisation; filtering with ANNOVAR; co-segregates within 2-generation family (n = 2, 2 affected (total 3)) | None | comp het with R14640C | 88 |
0.1587 | 0.256 | 0.401 | -0.202 | 0.891 | None | 0.563 | None | None | N | None | None | None | None | None | None | None | 29590 |
Fn3-103 |
58 | E/Q | rs72648236 |
gnomAD-4.0.0 | None | 0.00000159104 | None | 88 |
0.1587 | 0.256 | 0.401 | -0.202 | 0.891 | None | 0.563 | None | None | N | 0 | 0 | 0 | None | 0 | 2.85778E-06 | 0 | 31732 |
Fn3-119 |
25 | P/L | rs753334568 |
gnomAD-2.1.1 | None | 0.0000121 | None | 27 |
0.9061 | 0.727 | 0.888 | -0.671 | 1.0 | None | 0.1539 | None | None | N | 0 | 0 | 0 | None | 3.27E-05 | 0 | 1.78E-05 | 31732 |
Fn3-119 |
25 | P/L | rs753334568 |
gnomAD-3.1.2 | None | 0.0000131 | None | 27 |
0.9061 | 0.727 | 0.888 | -0.671 | 1.0 | None | 0.1539 | None | None | N | 0 | 0 | 0 | None | 0 | 2.94E-05 | 0 | 31732 |
Fn3-119 |
25 | P/L | rs753334568 |
Vasli (2012)
Pfeffer (2013)
Palmio (2013)
Hedberg (2014)
Yue (2015)
Rees (2021)
Sano (2022)
| Incomplete penetrance, more severe when homozygous; Found in genetic analysis of TTN in 30 CM patients (homozygous); genetic analysis of genes in 127 undiagnosed patients (likely MFM); WES/WGS prioritisation in 12 HMERF families; genetic analysis in single NMD patient (heterozygous); genetic analysis of CN patient (sporadic) and unaffected carrier (brother); Domain unfolded in vitro (Tm 17 degrees lower than WT) | None | hom / comp het with R34091W | 27 |
0.9061 | 0.727 | 0.888 | -0.671 | 1.0 | None | 0.1539 | None | None | N | None | None | None | None | None | None | None | 31732 |
Fn3-119 |
25 | P/L | rs753334568 |
gnomAD-4.0.0 | None | 0.00000929582 | None | 27 |
0.9061 | 0.727 | 0.888 | -0.671 | 1.0 | None | 0.1539 | None | None | N | 0 | 1.66706E-05 | 0 | None | 0 | 1.01715E-05 | 1.09786E-05 | 34072 |
Kinase-1 |
260 | W/R | rs375159973 |
gnomAD-2.1.1 | None | 0.00000811 | None | None |
0.9898 | 0.829 | None | -2.479 | None | None | 0.1071 | None | None | N | 0 | 0 | 0 | None | 0 | 0 | 1.78E-05 | 34072 |
Kinase-1 |
260 | W/R | rs375159973 |
gnomAD-3.1.2 | None | 0.0000197 | None | None |
0.9898 | 0.829 | None | -2.479 | None | None | 0.1071 | None | None | N | 0 | 0 | 0 | None | 0 | 4.41E-05 | 0 | 34072 |
Kinase-1 |
260 | W/R | rs375159973 |
Chauveau (2013)
Rees (2021)
| Genetic analysis of TTN in 30 CM patients; comp het with R7796*; Domain unfolded in vitro (Tm 17 degrees lower than WT); Also found by WES prioritisation in 23 families with congenital CM; comp het with E2989Efs*4; loss of interactions with protein binding partners (Y2H); recessive inheritance | None | comp het with E2989Efs*4 / comp het with R7796* | None |
0.9898 | 0.829 | None | -2.479 | None | None | 0.1071 | None | None | N | None | None | None | None | None | None | None | 34072 |
Kinase-1 |
260 | W/R | rs375159973 |
gnomAD-4.0.0 | None | 0.0000217264 | None | None |
0.9898 | 0.829 | None | -2.479 | None | None | 0.1071 | None | None | N | 0 | 1.66683E-05 | 2.22866E-05 | None | 0 | 2.62758E-05 | 1.09789E-05 | 35643 |
Ig-167 |
37 | V/I | rs754459138 |
gnomAD-2.1.1 | None | 0.0000607 | None | 55 |
0.0561 | 0.031 | 0.202 | -0.006 | 0.001 | None | 0.4132 | None | None | N | 0 | 0 | 4.61302E-04 | None | 0 | 0 | 6.24E-05 | 35643 |
Ig-167 |
37 | V/I | rs754459138 |
gnomAD-3.1.2 | None | 0.0000394 | None | 55 |
0.0561 | 0.031 | 0.202 | -0.006 | 0.001 | None | 0.4132 | None | None | N | 0 | 0 | 3.85208E-04 | None | 0 | 5.88E-05 | 0 | 35643 |
Ig-167 |
37 | V/I | rs754459138 |
Luo (2022)
| Genetic analysis of Hui (CN) HCM family; variant prioritisation in individuals without established pathology; significant echocardiographical differences reported between carrier (n = 4) and non-carrier (n = 12) individuals | None | het | 55 |
0.0561 | 0.031 | 0.202 | -0.006 | 0.001 | None | 0.4132 | None | None | N | None | None | None | None | None | None | None | 35643 |
Ig-167 |
37 | V/I | rs754459138 |
gnomAD-4.0.0 | None | 0.0000985272 | None | 55 |
0.0561 | 0.031 | 0.202 | -0.006 | 0.001 | None | 0.4132 | None | None | N | 0 | 0 | 2.00526E-04 | None | 0 | 1.25439E-04 | 0 |