SCN5A Variant R975W

Summary of observed carriers, functional annotations, and structural context for SCN5A R975W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

10%

1/20 effective observations

Estimated BrS1 penetrance

1/20 effective observations

Total carriers

0 BrS1 · 1 LQT3 · 9 unaffected

R975W is present in 8 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 (%)
-4.66	1	-1.22	0.629	13	5

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
19322600	2009	1		0	0	1	SIDS
26669661	2016	2		1	0	0
27816319	2017	2		2	0	0
20129283	2010	1		0	0	0
Literature, cohort, and gnomAD	–	10	9	1	0		–
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). V_1/2 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)	V_1/2 Activation (mV)	V_1/2 Inactivation (mV)	Late/Persistent Current (% WT)
20129283	2010
19322600	2009
26669661	2016
27816319	2017

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 R975W.
Neighbour residue	Distance (Å)	Observed variants
960	15	Q960K,
961	14
962	14
963	13
964	13	A964G,
965	12	R965C, R965H, R965L,
966	11
967	11	Q967R,
968	10
969	9	G969C, G969S,
970	8
971	8	R971C, R971H,
972	7	c.2914_2923delTTTGTCAAGC,
973	5
974	4	K974D,
975	0	R975W, R975Q,
976	4
977	5
978	7
979	8	D979H,
980	8
981	9	C981F,
982	10	C982R,
983	11	G983D,
984	11
985	12
986	13	R986L, R986W, R986Q,
987	13
988	14	R988Q, R988W,
989	14
990	15