SCN5A Variant c.999-424_1338+81del

Summary of observed carriers, functional annotations, and structural context for SCN5A c.999-424_1338+81del. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

14%

0/12 effective observations

Estimated BrS1 penetrance

41%

4/12 effective observations

Total carriers

2

1 BrS1 · 0 LQT3 · 1 unaffected

c.999-424_1338+81del 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 3 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 (%)
NA NA NA None 55 23

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
21288276 2011 2 0 1 0
Literature, cohort, and gnomAD 2 1 0 1
Variant features alone 15 12 0 3

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)
21288276 2011

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 c.999-424_1338+81del.
Neighbour residue Distance (Å) Observed variants
328 7
333 3 c.998+1G>A, c.998+5G>A,
326 5
276 15 L276P, L276Q,
387 12
279 13
385 10 A385T,
338 12
330 9 S330F,
278 11 H278R, H278D,
388 15 I388S,
334 0 c.999-424_1338+81del,
332 5 A332T,
327 5
339 10
1688 15
384 9 S384T,
1684 14 W1684R, W1684R,
329 8
1692 12
386 11 G386E, G386R, G386R,
340 12 R340W, R340Q,
1693 13
1699 13
331 8
379 13
341 9 C341Y,
335 4 C335S, C335S, C335R,
325 9 L325R,
1690 9 D1690N, c.5068_5070delGA,
324 10
275 14 N275K, N275K,
383 7
280 9 C280Y,
323 13
382 11
337 11
1689 10 D1689N,
342 13
336 7 P336L,
381 13 c.1140+1G>A, c.1141-3C>A,
1691 8
380 13
281 13 V281M,