SCN5A Variant E1784K
Summary of observed carriers, functional annotations, and structural context for SCN5A E1784K. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT3 penetrance
69%
116/174 effective observations
Estimated BrS1 penetrance
19%
32/174 effective observations
Total carriers
164
31 BrS1 · 114 LQT3 · 19 unaffected
Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 2 individuals for LQT3.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density BrS (%) | Penetrance Density LQT3 (%) |
|---|---|---|---|---|---|
| -3.57 | 0.82 | 0.04 | 0.91 | 20 | 61 |
PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).
Reported carrier data
| Source | Year | Carriers | Unaffected | LQT3 | BrS1 | Other | Other Disease |
|---|---|---|---|---|---|---|---|
| 24439875 | 2014 | 4 | 1 | 2 | 1 | Sino-atrial block | |
| 18451998 | 2008 | 50 | 38 | 9 | 0 | ||
| 27381756 | 2016 | 17 | 10 | 7 | 0 | ||
| 10961955 | 2000 | 3 | 3 | 0 | 0 | ||
| 10973849 | 2000 | 1 | 1 | 0 | 0 | ||
| 11901046 | 2002 | 1 | 0 | 1 | 0 | ||
| 12877697 | 2003 | 3 | 3 | 0 | 0 | ||
| 15840476 | 2005 | 4 | 4 | 0 | 0 | ||
| 16379539 | 2005 | 2 | 2 | 0 | 0 | ||
| 17971661 | 2008 | 8 | 5 | 2 | 0 | ||
| 18452873 | 2008 | 2 | 1 | 0 | 1 | AF | |
| 18508782 | 2008 | 10 | 0 | 9 | 1 | SD | |
| 19181867 | 2009 | 1 | 0 | 1 | 0 | ||
| 20123697 | 2010 | 1 | 0 | 1 | 0 | ||
| 20541041 | 2010 | 8 | 8 | 0 | 0 | ||
| 20566482 | 2010 | 1 | 0 | 1 | 0 | ||
| 20659946 | 2010 | 4 | 4 | 0 | 0 | ||
| 21321465 | 2011 | 1 | 0 | 1 | 0 | ||
| 22360817 | 2012 | 13 | 13 | 0 | 0 | ||
| 23098067 | 2012 | 1 | 1 | 0 | 0 | ||
| 23631430 | 2013 | 1 | 1 | 0 | 0 | ||
| 24667783 | 2015 | 1 | 1 | 0 | 0 | ||
| 24762805 | 2014 | 4 | 4 | 0 | 0 | BrS (overlap), SSS | |
| 26669661 | 2016 | 34 | 20 | 0 | 0 | ||
| 26729854 | 2016 | 1 | 0 | 1 | 0 | ||
| 26921764 | 2016 | 9 | 0 | 9 | 0 | ||
| 26940925 | 2016 | 1 | 1 | 0 | 0 | ||
| 28341781 | 2017 | 2 | 0 | 2 | 0 | ||
| 28781849 | 2017 | 2 | 0 | 1 | 0 | ||
| 24871449 | 2014 | 14 | 14 | 0 | 0 | ||
| 25904541 | 2015 | 3 | 3 | 0 | 0 | ||
| 27566755 | 2016 | 70 | 70 | 0 | 0 | ||
| 27915266 | 2017 | 16 | 16 | 0 | 0 | ||
| 27677334 | 2016 | 1 | 1 | 0 | 0 | ||
| 10377081 | 1999 | 4 | 4 | 0 | 0 | ||
| 19716085 | 2009 | 15 | 15 | 0 | 0 | ||
| 20129283 | 2010 | 14 | 0 | 14 | 0 | ||
| 10727653 | 2000 | 1 | 1 | 0 | 0 | ||
| 29325976 | 2018 | 4 | 0 | 4 | 0 | ||
| 30059973 | 2018 | 69 | 69 | 0 | 0 | ||
| Literature, cohort, and gnomAD | – | 164 | 19 | 114 | 31 | – | |
| Variant features alone | – | 15 | 12 | 2 | 1 | – | – |
Totals may differ from individual publications due to duplicate patients removed during curation.
Functional data
Peak and late/persistent current values are relative to wild-type (100% indicates no change). V1/2 activation and inactivation denote the membrane potentials (mV) at which half-maximal current is achieved.
| PubMed ID | Year | Cell Type | Peak Current (% WT) | V1/2 Activation (mV) | V1/2 Inactivation (mV) | Late/Persistent Current (% WT) |
|---|---|---|---|---|---|---|
| 29325976 | 2018 | |||||
| 30059973 | 2018 | |||||
| 26131924 | 2015 | CHO | 106 | -0.16 | -16.19 | 405 |
| 24439875 | 2014 | tsA201 | 39 | 0 | -18.4 | 1436 |
| 10727653 | 2000 | HEK-tSA201 | 8.8 | -14.4 | 500 | |
| 32533946 | 2020 | HEK | 52 | -5.4 | ||
| 20129285 | 2010 | |||||
| 18451998 | 2008 | tsA201 | 60 | 12.5 | -15 | 348 |
| 29483621 | 2018 | HEK | 144 | 5.32 | -11.84 | 50 |
| 10727647 | 2000 | |||||
| 10961955 | 2000 | |||||
| 10973849 | 2000 | |||||
| 11901046 | 2002 | |||||
| 12877697 | 2003 | |||||
| 15840476 | 2005 | |||||
| 27381756 | 2016 | tsA201 | 70 | -11.03 | 0 | |
| 16379539 | 2005 | |||||
| 17971661 | 2008 | |||||
| 18452873 | 2008 | |||||
| 19181867 | 2009 | |||||
| 20123697 | 2010 | |||||
| 20541041 | 2010 | |||||
| 20566482 | 2010 | |||||
| 18508782 | 2008 | |||||
| 20659946 | 2010 | |||||
| 21321465 | 2011 | |||||
| 22360817 | 2012 | |||||
| 23098067 | 2012 | |||||
| 23631430 | 2013 | |||||
| 24667783 | 2015 | |||||
| 24762805 | 2014 | |||||
| 26669661 | 2016 | |||||
| 26729854 | 2016 | |||||
| 26921764 | 2016 | |||||
| 26940925 | 2016 | |||||
| 28341781 | 2017 | |||||
| 28781849 | 2017 | |||||
| 29017927 | 2017 | |||||
| 24871449 | 2014 | |||||
| 24920323 | 2014 | |||||
| 25904541 | 2015 | |||||
| 27566755 | 2016 | |||||
| 27915266 | 2017 | |||||
| 28412158 | 2017 | |||||
| 20188230 | 2010 | |||||
| 28734073 | 2017 | HEK | ||||
| 27677334 | 2016 | hiPSC | ||||
| 28898267 | 2017 | Oocytes | ||||
| 10377081 | 1999 | Xeno | NA | -12.1 | 1000 | |
| 19716085 | 2009 | |||||
| 20129283 | 2010 |
Nearby variants
Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.
| Neighbour residue | Distance (Å) | Observed variants |
|---|---|---|
| 1785 | 4 | |
| 1778 | 12 | |
| 1866 | 8 | |
| 1824 | 11 | P1824A, |
| 1777 | 12 | V1777L, V1777M, V1777L, |
| 1492 | 11 | |
| 1491 | 11 | Q1491H, Q1491H, |
| 1863 | 9 | |
| 1501 | 15 | p.L1501_K1505del, L1501V, |
| 1860 | 14 | c.5577_5578dupAA, |
| 1874 | 14 | |
| 1862 | 6 | |
| 1779 | 11 | T1779M, |
| 1493 | 6 | K1493X, K1493R, p.K1493del, |
| 1867 | 11 | |
| 1858 | 11 | |
| 1865 | 6 | |
| 1776 | 14 | |
| 1787 | 11 | S1787N, |
| 1786 | 8 | L1786Q, c.5356_5357delCT, L1786R, |
| 1861 | 9 | V1861I, V1861F, |
| 1495 | 14 | Y1495S, |
| 1864 | 11 | |
| 1496 | 11 | |
| 1870 | 15 | A1870T, |
| 1825 | 14 | L1825P, |
| 1781 | 8 | E1781D, E1781G, E1781D, |
| 1488 | 12 | T1488R, |
| 1784 | 0 | E1784K, E1784X, |
| 1498 | 13 | M1498R, M1498T, M1498V, |
| 1780 | 8 | E1780G, |
| 1500 | 13 | p.K1500del, |
| 1859 | 12 | |
| 1869 | 13 | |
| 1791 | 14 | |
| 1868 | 8 | |
| 1823 | 15 | p.E1823HfsX10, E1823K, |
| 1783 | 5 | |
| 1497 | 10 | |
| 1490 | 7 | |
| 1790 | 13 | p.D1790del, D1790N, D1790G, |
| 1494 | 9 | |
| 1489 | 11 | E1489D, E1489D, |
| 1782 | 8 |