SCN5A Variant I1593M

Summary of observed carriers, functional annotations, and structural context for SCN5A I1593M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

38%

2/12 effective observations

Estimated BrS1 penetrance

6%

0/12 effective observations

Total carriers

2

0 BrS1 · 1 LQT3 · 1 unaffected

I1593M is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for Brugada syndrome and a Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 0 individuals for Brugada syndrome and 1 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.57 0.998 -1.11 0.892 1 47

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
19716085 2009 1 1 0 0
Literature, cohort, and gnomAD – 2 1 1 0 –
Variant features alone – 15 14 1 0 – –

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)
25904541 2015 HEK 111 -4 2 90
19716085 2009

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 I1593M.
Neighbour residue Distance (Å) Observed variants
1586 6
1624 14 V1624I,
1635 14
1587 6 F1587V,
1602 15
1601 13 L1601H,
1575 10 C1575S, C1575S,
1600 11
1571 14 F1571C,
1572 15
1599 11
1583 14 R1583C, R1583H,
1580 15
1630 15 I1630V, I1630R,
1626 15 R1626C, R1626H, R1626P, R1626L,
1625 11
1585 13 Y1585C,
1576 15
1596 6 F1596I, F1596C,
1628 11
1589 6
1584 12
1632 11 R1632C, R1632H, R1632L
1597 7 V1597M,
1594 5 F1594S,
1588 8 T1588I,
1581 15 A1581S,
1591 8 W1591X,
1593 0 I1593M,
1595 7
1629 10 R1629G, R1629X, R1629Q,
1574 12 c.4719C>T, E1574K,
1592 5
1578 11 c.4732_4733dupAA,
1631 13 G1631D,
1590 5
1622 15
1582 12 L1582P,
1579 11 L1579fsX53,
1598 10 V1598A,
1577 15