SCN5A Variant V125L

Summary of observed carriers, functional annotations, and structural context for SCN5A V125L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

2%

1/65 effective observations

Estimated BrS1 penetrance

3%

2/65 effective observations

Total carriers

55

0 BrS1 · 1 LQT3 · 54 unaffected

V125L is present in 54 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 2 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 (%)
-1.33 0.264 -0.05 0.603 34 1

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
15840476 2005 1 1 0 0
27566755 2016 1 1 0 0
19716085 2009 1 1 0 0
29396286 2018 1 0 0 1 electrical storm
Literature, cohort, and gnomAD – 55 54 1 0 –
Variant features alone – 15 13 0 2 – –

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)
25904541 2015 HEK 71 4 4 157
29396286 2018
23805106 2013 HEK 83 0.7 3.1 36
15840476 2005
27566755 2016
19716085 2009

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 V125L.
Neighbour residue Distance (Å) Observed variants
126 5 K126E,
175 9 K175N, K175N,
113 14 V113A, V113I
129 6
188 13
178 5 A178G,
128 6 c.381dupT,
117 13
179 7 R179Q, R179X,
119 10 P119L, P119S,
177 8 L177P,
123 5 A123V, A123G,
121 6 R121Q, R121W,
127 6
124 4 A124D,
118 11
125 0 V125L, V125L,
176 11
172 13
131 13
174 8 V174I,
133 10
115 12 S115G,
173 11
132 14 c.393-5C>A,
112 13 Y112C,
114 11
130 10
184 13 H184R,
116 10
180 11 G180V,
134 12 N134S,
170 13 F170I,
120 9
122 7
171 13