SCN5A Variant P648L
Summary of observed carriers, functional annotations, and structural context for SCN5A P648L. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT3 penetrance
10%
2/27 effective observations
Estimated BrS1 penetrance
10%
2/27 effective observations
Total carriers
17
1 BrS1 · 2 LQT3 · 14 unaffected
Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 0 individuals for LQT3.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density BrS (%) | Penetrance Density LQT3 (%) |
|---|---|---|---|---|---|
| 0.47 | 0.011 | -0.49 | 0.485 | 18 | 6 |
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 |
|---|---|---|---|---|---|---|---|
| 24613995 | 2014 | 1 | 0 | 0 | 1 | irritable bowel syndrome | |
| 15840476 | 2005 | 1 | 1 | 0 | 0 | ||
| 19412328 | 2008 | 1 | 0 | 0 | 1 | DCM | |
| 23631430 | 2013 | 1 | 1 | 0 | 0 | ||
| 26941339 | 2016 | 1 | 0 | 1 | 0 | ||
| 25904541 | 2015 | 1 | 1 | 0 | 0 | ||
| 20129283 | 2010 | 1 | 0 | 1 | 0 | ||
| Literature, cohort, and gnomAD | – | 17 | 14 | 2 | 1 | – | |
| Variant features alone | – | 15 | 14 | 0 | 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.
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 |
|---|---|---|
| 633 | 15 | |
| 634 | 14 | S634W, S634L, |
| 635 | 14 | |
| 636 | 13 | E636K, |
| 637 | 13 | P637L, |
| 638 | 12 | G638D, |
| 639 | 11 | G639A, G639R |
| 640 | 11 | P640A, P640S, P640L, |
| 641 | 10 | |
| 642 | 9 | |
| 643 | 8 | |
| 644 | 8 | |
| 645 | 7 | |
| 646 | 5 | c.1936delC, p.Q646RfsX5, |
| 647 | 4 | A647V, A647D, A647S, |
| 648 | 0 | P648L, |
| 649 | 4 | C649R, C649Y, |
| 650 | 5 | |
| 651 | 7 | D651H, c.1950_1953delAGAT, |
| 652 | 8 | G652S, G652D, |
| 653 | 8 | |
| 654 | 9 | E654D, E654Q, E654K, E654X , |
| 655 | 10 | E655K, |
| 656 | 11 | P656L, |
| 657 | 11 | |
| 658 | 12 | A658V, |
| 659 | 13 | R659W, R659Q, |
| 660 | 13 | |
| 661 | 14 | R661Q, R661W, |
| 662 | 14 | c.1983_1993dupGGCCCTCAGCG, A662S, |
| 663 | 15 |