SCN5A Variant R1644H
Summary of observed carriers, functional annotations, and structural context for SCN5A R1644H. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT3 penetrance
64%
18/34 effective observations
Estimated BrS1 penetrance
7%
2/34 effective observations
Total carriers
24
1 BrS1 · 17 LQT3 · 6 unaffected
Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 1 individuals for LQT3.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density BrS (%) | Penetrance Density LQT3 (%) |
|---|---|---|---|---|---|
| -4.56 | 0.995 | -0.14 | 0.974 | 22 | 38 |
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 |
|---|---|---|---|---|---|---|---|
| 26803770 | 2016 | 15 | 10 | 0 | 0 | ||
| 8541846 | 1995 | 2 | 2 | 0 | 0 | ||
| 15051636 | 2004 | 2 | 1 | 0 | 0 | ||
| 15840476 | 2005 | 2 | 2 | 0 | 0 | ||
| 19026623 | 2009 | 1 | 1 | 0 | 0 | ||
| 20541041 | 2010 | 1 | 1 | 0 | 0 | ||
| 22360817 | 2012 | 1 | 1 | 0 | 0 | ||
| 23631430 | 2013 | 1 | 1 | 0 | 0 | ||
| 26669661 | 2016 | 16 | 11 | 0 | 0 | ||
| 26940925 | 2016 | 1 | 1 | 0 | 0 | ||
| 28341781 | 2017 | 1 | 0 | 1 | 0 | ||
| 25904541 | 2015 | 1 | 1 | 0 | 0 | ||
| 27566755 | 2016 | 2 | 2 | 0 | 0 | ||
| 29691127 | 2018 | 1 | 1 | 0 | 0 | ||
| 30059973 | 2018 | 2 | 2 | 0 | 0 | ||
| Literature, cohort, and gnomAD | – | 24 | 6 | 17 | 1 | – | |
| Variant features alone | – | 15 | 13 | 1 | 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) |
|---|---|---|---|---|---|---|
| 26803770 | 2016 | hiPSC-CM | 163 | |||
| 8541846 | 1995 | |||||
| 15051636 | 2004 | |||||
| 15840476 | 2005 | |||||
| 19026623 | 2009 | |||||
| 20541041 | 2010 | |||||
| 22360817 | 2012 | |||||
| 23631430 | 2013 | |||||
| 26669661 | 2016 | |||||
| 26940925 | 2016 | |||||
| 28341781 | 2017 | |||||
| 29017927 | 2017 | |||||
| 25904541 | 2015 | |||||
| 27566755 | 2016 | |||||
| 8917568 | 1996 | Oocytes | -6.4 | -2.5 | 800 | |
| 29691127 | 2018 | |||||
| 30059973 | 2018 |
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 |
|---|---|---|
| 1643 | 7 | I1643L, |
| 1778 | 12 | |
| 1653 | 15 | |
| 1635 | 10 | |
| 1652 | 12 | M1652T, M1652R, |
| 1634 | 8 | L1634P, |
| 1650 | 11 | L1650F, |
| 1641 | 6 | |
| 1639 | 7 | G1639A, |
| 1779 | 13 | T1779M, |
| 1787 | 10 | S1787N, |
| 1654 | 15 | |
| 1786 | 14 | c.5356_5357delCT, L1786Q, L1786R, |
| 1648 | 7 | |
| 1649 | 10 | A1649V, |
| 1644 | 0 | R1644C, R1644H, R1644L, |
| 1640 | 7 | |
| 256 | 12 | |
| 1793 | 11 | M1793K, |
| 1781 | 14 | E1781G, E1781D, E1781D, |
| 1789 | 6 | |
| 1632 | 15 | R1632C, R1632H, R1632L, |
| 255 | 13 | |
| 1645 | 5 | T1645M, |
| 1796 | 13 | |
| 1788 | 10 | c.5361_5364delTGAG, |
| 1638 | 6 | R1638X, R1638Q, |
| 1651 | 9 | |
| 259 | 14 | |
| 1633 | 11 | |
| 1791 | 13 | |
| 1637 | 5 | |
| 253 | 13 | |
| 1792 | 10 | D1792N, D1792Y, D1792V, |
| 1636 | 9 | |
| 407 | 15 | |
| 1775 | 13 | F1775V, p.F1775LfsX15, |
| 1642 | 7 | G1642E, |
| 1790 | 10 | D1790N, D1790G, p.D1790del, |
| 1631 | 13 | G1631D, |
| 252 | 12 | |
| 1647 | 6 | |
| 1822 | 14 | c.5464_5467delTCTG, c.5464-5467delTCTG |
| 1646 | 8 | |
| 1782 | 12 |