SCN5A Variant M138I

Summary of observed carriers, functional annotations, and structural context for SCN5A M138I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

0/11 effective observations

Estimated BrS1 penetrance

16%

1/11 effective observations

Total carriers

1

0 BrS1 · 0 LQT3 · 1 unaffected

M138I is present in 1 alleles in gnomAD. This residue resides in a 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 (%)
-3.17 0.801 2.72 0.886 21 0

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
18378609 2008 1 0 0 1 AF
Literature, cohort, and gnomAD – 1 1 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)
18378609 2008

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 M138I.
Neighbour residue Distance (Å) Observed variants
848 13 I848F,
223 14 V223L,
231 8 c.692_693delCA,
131 11
193 13 W193R, W193R, W193X,
164 12 F164L, F164L, F164L,
130 13
170 15 F170I,
228 7 K228R,
138 0 M138I, M138I, M138I,
227 11 L227P,
171 10
143 9
137 5 I137V,
234 14 P234S,
142 6
197 11
229 6
129 14
851 15 c.2552_2553dupGT, F851L, F851L, p.F851CfsX19, F851L, c.2550_2551dupGT,
196 13
224 14 L224F,
845 15 c.2533delG,
232 7 V232F, V232I,
133 9
132 11 c.393-5C>A,
134 7 N134S,
226 9 A226V, A226G,
144 10
172 15
230 10 I230M, I230T, I230V,
139 5 p.I137_C139dup,
148 15
165 15
236 14
146 13 V146A, V146M,
136 7 L136P,
168 10
175 13 K175N, K175N,
233 11
194 14
141 5 I141N, I141V,
135 7 M135V,
167 11
128 13 c.381dupT,
201 14
225 8 R225W, R225Q,
844 14 L844RfsX3,
200 14
145 10
140 7