SCN5A Variant E346D

Summary of observed carriers, functional annotations, and structural context for SCN5A E346D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

0/11 effective observations

Estimated BrS1 penetrance

28%

3/11 effective observations

Total carriers

1

1 BrS1 · 0 LQT3 · 0 unaffected

E346D has not been reported in gnomAD. This residue resides in a Non_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 (%)
-1.28 0 0.17 0.299 32 2

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
16643399 2006 1 0 1 0
Literature, cohort, and gnomAD – 1 0 0 1 –
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)
32533946 2020 HEK 113 -7.6 -4.1
16643399 2006

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 E346D.
Neighbour residue Distance (Å) Observed variants
277 7
276 11 L276Q, L276P,
348 8 P348A,
317 11 K317N, K317M, K317E, K317N,
360 12
279 9
355 14 F355C, F355I,
278 12 H278R, H278D,
356 11 D356N,
318 15
904 13 W904X,
343 11
871 15
354 10
349 10 D349N,
1550 12
357 14
274 11 G274C,
273 15
319 13 G319C, G319R, G319S,
325 12 L325R,
324 14
321 8 S321Y,
872 14 D872N,
345 4
275 14 N275K, N275K,
280 14 C280Y,
912 15 Q912R,
323 10
347 5
351 6 G351D, G351V, G351C, G351S,
320 10 T320N,
350 10 H350Q, H350Q,
342 13
1551 14 D1551N, D1551Y,
346 0 E346X, E346G, E346D, E346D, E346K,
344 7 A344S,
322 9
352 9 Y352C,
380 14
908 13
281 13 V281M,
353 10 T353I,