SCN5A Variant R104W

Summary of observed carriers, functional annotations, and structural context for SCN5A R104W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

18%

1/13 effective observations

Estimated BrS1 penetrance

46%

6/13 effective observations

Total carriers

3

2 BrS1 · 0 LQT3 · 1 unaffected

R104W is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 4 individuals for Brugada syndrome and 1 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.59 1 -0.38 0.95 51 31

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
22739120 2012 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
Literature, cohort, and gnomAD – 3 1 0 2 –
Variant features alone – 15 10 1 4 – –

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)
22739120 2012 HEK 0
20129283 2010
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.

Previously observed variants near R104W.
Neighbour residue Distance (Å) Observed variants
89 15
90 14 p.Q90WfsX14,
91 14
92 13 c.274-24C>T, T92I,
93 13 F93S,
94 12 I94V, I94S,
95 11 V95I, V95L, V95L,
96 11
97 10
98 9
99 8
100 8
101 7 T101I,
102 5
103 4
104 0 R104G, R104W, R104Q,
105 4
106 5 S106T,
107 7
108 8
109 8 N109K, N109K,
110 9 A110T,
111 10
112 11 Y112C,
113 11 V113I, V113A,
114 12
115 13 S115G,
116 13
117 14
118 14
119 15 P119S, P119L