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

P648L is present in 14 alleles in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 0 individuals for LQT3.

In silico predictors

Variant-level computational 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

Observed carriers by publication or cohort.
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.

Published electrophysiology measurements.
PubMed ID Year Cell Type Peak Current (% WT) V1/2 Activation (mV) V1/2 Inactivation (mV) Late/Persistent Current (% WT)
15840476 2005
19412328 2008
23631430 2013
26941339 2016
25904541 2015
20129283 2010
24613995 2014 HEK 99 2 -0.5 45

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.

Previously observed variants near P648L.
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