SCN5A Variant M369K

Summary of observed carriers, functional annotations, and structural context for SCN5A M369K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

9%

0/13 effective observations

Estimated BrS1 penetrance

62%

8/13 effective observations

Total carriers

3

3 BrS1 · 0 LQT3 · 0 unaffected

M369K has not been reported 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 5 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 (%)
-5.89 0.963 -3.37 0.986 71 18

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
12106943 2002 1 0 1 0
16643399 2006 1 0 1 0
17404158 2007 1 0 1 0
26921764 2016 3 0 3 0
20129283 2010 1 0 1 0
30059973 2018 3 3 0 0
Literature, cohort, and gnomAD 3 0 0 3
Variant features alone 15 10 0 5

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)
30059973 2018
12106943 2002
16643399 2006
17404158 2007
26921764 2016
20129283 2010
32533946 2020 HEK 3

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 M369K.
Neighbour residue Distance (Å) Observed variants
403 10
364 9
363 11
404 6 L404V, L404Q,
396 7 V396L, V396A,
355 14 F355C, F355I,
254 11
372 10
1771 14 I1771T,
401 4 S401P,
1764 15 V1764F, c.5290delG,
371 7 Q371E,
250 14
409 14 L409P, L409V,
928 10 L928P,
1650 15 L1650F,
361 12
260 9
366 5
365 6
258 11 V258A,
897 12 G897E, G897R,
924 12 V924I,
927 12 N927K, N927S,
369 0 M369K,
1767 14 Y1767C,
402 9 F402L,
373 13
1768 14 I1768V,
267 14
262 12 S262G,
256 11
399 10
397 7 I397V, I397T, I397F,
405 7
362 10
261 7
920 12
1709 12 p.T1709del, T1709M, T1709R,
900 14
392 12
255 14
395 11
393 11
394 13
264 9
259 13
265 11 A265V,
408 11
374 11 W374G,
253 12
407 11
367 9 R367C, R367H, R367L,
263 12 V263I,
370 5 T370M,
923 11
406 10 N406S, N406K,
368 6
899 11
268 14 G268S,
377 13
932 14
398 11
257 8
400 5 G400A, G400E, G400R,