SCN5A Variant I1660V

Summary of observed carriers, functional annotations, and structural context for SCN5A I1660V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

11%

2/27 effective observations

Estimated BrS1 penetrance

34%

9/27 effective observations

Total carriers

17

5 BrS1 · 2 LQT3 · 10 unaffected

I1660V is present in 8 alleles in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 4 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 (%)
-0.89 0.986 4.88 0.837 60 6

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
24269159 2013 2 0 1 0
17075016 2006 3 0 1 0
16414944 2005 1 1 0 0
20812931 2011 1 0 1 0
23631430 2013 1 1 0 0
26173111 2015 1 0 1 0
20129283 2010 4 0 4 0
20129283 2010 4 0 4 0
29709244 2018 2 0 1 0
29759671 2018 1 0 1 0
30059973 2018 2 2 0 0
Literature, cohort, and gnomAD – 17 10 2 5 –
Variant features alone – 15 11 0 4 – –

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)
24269159 2013 HEK 0
17075016 2006 HEK-tSA201 3 NA NA 0
16414944 2005
20812931 2011
23631430 2013
26173111 2015
20129283 2010
20129283 2010
29709244 2018
29759671 2018
30059973 2018

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 I1660V.
Neighbour residue Distance (Å) Observed variants
403 11
1328 14 V1328M,
1659 5
1773 14
1765 10
1653 10
1472 15 p.N1472del, N1472S,
1315 12
1771 11 I1771T,
401 14 S401P,
1652 15 M1652T, M1652R,
1314 10 c.3940_3941delCT,
1320 7 M1320I, M1320I, M1320I,
1764 8 c.5290delG, V1764F,
1666 11
1650 14 L1650F,
1656 6
1477 14 K1477N, K1477N,
1762 10 p.I1762del, I1762M,
1470 14
1668 12 M1668T,
1466 14 c.4396_4397insG,
1767 6 Y1767C,
1313 14
1660 0 I1660V, I1660S,
1654 11
1769 10
402 10 F402L, F402L, F402L,
1766 6 M1766L, M1766V, M1766L, M1766T,
1319 9 G1319V,
1665 11
1768 10 I1768V,
1774 14 N1774D, c.5321_5324dupACTT
1473 11 F1473S, F1473C,
1663 5
399 12
397 14 I397V, I397F, I397T,
1657 6
1759 10 S1759C,
1662 7
1324 10
1317 11 F1317C,
1327 10
1709 14 p.T1709del, T1709R, T1709M,
1758 12 I1758V, p.I1758del,
1755 14
1318 13
1330 15 A1330T, A1330P, A1330D,
1772 14 L1772V,
1321 13 R1321K,
1323 6 V1323G,
394 13
1770 8 I1770V,
1708 12 T1708I,
1705 14
1322 10 c.3963+2T>C, c.3963+4A>G,
1326 11 A1326S,
1763 6 V1763M, V1763L, V1763L,
1311 13 L1311P,
1760 14
1476 14 Q1476X, Q1476R,
1670 15
1661 4 G1661R, G1661R, G1661E,
1761 14 c.5280delG, L1761F, L1761H,
1655 9
1469 12 I1469V,
406 13 N406S, N406K, N406K,
1325 13 N1325S,
398 9
400 14 G400R, G400R, G400E, G400A,
1667 10 V1667I,
1664 6
1658 8