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SCN5A Variant D356N

Summary of observed carriers, functional annotations, and structural context for SCN5A D356N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

3%

0/20 effective observations

Estimated BrS1 penetrance

71%

14/20 effective observations

Total carriers

10

9 BrS1 · 0 LQT3 · 1 unaffected

D356N 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 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 (%)
-4.91 1 -1.11 0.961 74 9

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
16325048 2005 1 0 1 0
22885917 2012 2 0 2 0
26173111 2015 1 0 1 0
20129283 2010 8 0 8 0
29325976 2018 2 0 2 0
29325976 2018 2 0 2 0
29574140 2018 1 0 1 0
30059973 2018 3 3 0 0
Literature, cohort, and gnomAD 10 1 0 9
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)
16325048 2005 HEK 0
22885917 2012
26173111 2015
20129285 2010
20188230 2010
20129283 2010
29325976 2018
29325976 2018
29574140 2018
30059973 2018

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 D356N.
Neighbour residue Distance (Å) Observed variants
364 11
277 7
271 12 L271V,
266 11 L266H,
276 9 L276Q, L276P,
363 12
348 12 P348A,
270 10 Q270K,
360 7
279 15
1552 10 Q1552L, Q1552R
355 7 F355C, F355I,
1549 6
278 13 H278D, H278R,
1556 15
356 0 D356N,
361 7
904 15 W904X,
343 11
365 13
384 15 S384T,
354 5
1546 12 M1546T,
1545 13
349 15 D349N,
267 13
1550 6
357 4
272 9
274 7 G274C,
362 12
273 6
1553 14 S1553R,
269 7
345 12
275 10 N275K,
912 15 Q912R,
347 9
1548 9 G1548K, E1548K,
351 10 G351D, G351C, G351S, G351V,
265 11 A265V,
350 15 H350Q,
358 9
1551 9 D1551Y, D1551N,
346 11 E346D, E346X, E346G, E346K,
359 8 A359T, p.A359PfsX12,
1547 11 V1547L,
344 12 A344S,
381 14 c.1140+1G>A, c.1141-3C>A,
352 10 Y352C,
380 15
268 9 G268S,
377 14
353 9 T353I,
1623 15 c.4867delC, R1623Q, R1623L, R1623X,