SCN5A Variant M858L

Summary of observed carriers, functional annotations, and structural context for SCN5A M858L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

0/13 effective observations

Estimated BrS1 penetrance

12%

1/13 effective observations

Total carriers

3

0 BrS1 · 0 LQT3 · 3 unaffected

M858L is present in 2 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 (%)
-2.54 0.833 1.46 0.936 16 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
24948852 2014 3 0 0 2 SSS
Literature, cohort, and gnomAD – 3 3 0 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). 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)
24948852 2014

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 M858L.
Neighbour residue Distance (Å) Observed variants
891 11 I891N, I891T,
880 10
888 11
154 12 P154L,
223 10 V223L,
856 7 V856L, V856L,
890 10 I890T,
919 13
862 6
867 14 E867K, E867Q, E867X,
859 5
153 13
149 9
147 13
863 10
887 6
156 13 W156R, W156R, W156X,
864 11
886 10 H886P, H886Q, H886Q,
216 12 S216X, S216L,
851 10 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 12
909 15
852 11
854 6 c.2559delT,
222 12 R222X, R222Q, R222L,
224 14 L224F,
876 14
857 5 G857D,
150 12
902 14
882 7
881 6
226 15 A226G, A226V,
860 8 p.L860fsx89,
889 12
858 0 M858L, M858L,
144 13
217 13
918 13
855 5
865 10
148 9
884 7
906 13
866 12 S866P, S866L,
910 14 S910L,
885 11
146 14 V146M, V146A,
152 8 D152N,
853 11
219 10 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
877 14
151 8
879 14 W879R, W879R,
218 15
883 7
915 13 C915R
850 12 V850M, c.2549_2550insTG,
914 14
145 12
861 8 p.F861WfsX90, c.2582_2583delTT,
220 9 T220I,