SCN5A Variant R458H

Summary of observed carriers, functional annotations, and structural context for SCN5A R458H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

3%

0/12 effective observations

Estimated BrS1 penetrance

4%

0/12 effective observations

Total carriers

2

0 BrS1 · 0 LQT3 · 2 unaffected

R458H is present in 2 alleles 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 0 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 (%)
-0.62 0.001 0.24 0.209 0 1

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
Literature, cohort, and gnomAD – 2 2 0 0 –
Variant features alone – 15 15 0 0 – –

Totals may differ from individual publications due to duplicate patients removed during curation.

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 R458H.
Neighbour residue Distance (Å) Observed variants
443 15
444 14 E444fsX14,
445 14 H445D, H445Y, H445Q, H445Q,
446 13 E446K,
447 13 c.1338+2T>A, c.1339-24G>A, A447S, A447G,
448 12
449 11 T449A, Y449C,
450 11
451 10
452 9 G452D,
453 8 V453M,
454 8
455 7
456 5 V456M,
457 4
458 0 p.R458VfsX12, R458C, R458H,
459 4 S459G,
460 5
461 7 L461V,
462 8 E462K, E462A,
463 8 M463T, M463R,
464 9
465 10 p.P465LfsX5,
466 11 L466F, L466F,
467 11
468 12 P468L,
469 13 V469I,
470 13 N470K, N470K,
471 14
472 14
473 15 E473X