SCN5A Variant T512I

Summary of observed carriers, functional annotations, and structural context for SCN5A T512I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

0/13 effective observations

Estimated BrS1 penetrance

26%

3/13 effective observations

Total carriers

3

1 BrS1 · 0 LQT3 · 2 unaffected

T512I is present in 1 alleles in gnomAD. This residue resides in a Mild_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 (%)
-0.56 0.022 -0.83 0.54 32 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
12569159 2003 2 0 0 1 AV Block
27554632 2017 2 0 1 1 CM
Literature, cohort, and gnomAD – 3 2 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)
12569159 2003 HEK 100 -8.7 -7.5
12569154 2003
27554632 2017

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 T512I.
Neighbour residue Distance (Å) Observed variants
497 15 S497C,
498 14
499 14
500 13 E500K,
501 13 D501G,
502 12
503 11 P503S,
504 11 R504T,
505 10 A505E,
506 9 M506K,
507 8 p.N507_L515dup,
508 8
509 7
510 5
511 4
512 0 T512I,
513 4 R513C, c.1537delC, R513H, R513P,
514 5 G514C,
515 7
516 8
517 8 R517S, R517S,
518 9
519 10 S519F,
520 11 M520V, M520R,
521 11 K521E, c.1562delA,
522 12 P522S,
523 13 R523S, R523C, R523H,
524 13 c.1570_1571insG, S524Y,
525 14 S525G,
526 14 R526C, R526H,
527 15 G527R, G527R