SCN5A Variant N291H

Summary of observed carriers, functional annotations, and structural context for SCN5A N291H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

20%

1/14 effective observations

Estimated BrS1 penetrance

10%

1/14 effective observations

Total carriers

4

0 BrS1 · 1 LQT3 · 3 unaffected

N291H is present in 3 alleles in gnomAD. This residue resides in a Non_Hotspot region for Brugada syndrome and a Mild_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 (%)
-1.64 0.947 -0.82 0.586 7 19

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
17161064 2006 1 1 0 0
Literature, cohort, and gnomAD – 4 3 1 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)
17161064 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 N291H.
Neighbour residue Distance (Å) Observed variants
276 15 L276P, L276Q,
277 14
278 14 H278R, H278D,
279 13
280 13 C280Y,
281 12 V281M,
282 11 R282C, R282H,
283 11
284 10
285 9 T285K,
286 8 A286V, A286S,
287 8
288 7 N288S,
289 5 G289S,
290 4 p.T290_G292del,
291 0 N291S, p.N291TfsX52, N291H, N291K, p.N291_S293dup, N291K
292 4 G292S,
293 5
294 7 V294M,
295 8 E295K,
296 8
297 9
298 10 G298S, G298D,
299 11 L299M, L299F, L299F,
300 11 V300I,
301 12
302 13
303 13
304 14
305 14 D305N,
306 15 L306F, L306V,