SCN5A Variant M1766L

Summary of observed carriers, functional annotations, and structural context for SCN5A M1766L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

66%

3/11 effective observations

Estimated BrS1 penetrance

16%

1/11 effective observations

Total carriers

1

0 BrS1 · 1 LQT3 · 0 unaffected

M1766L has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 2 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.74 0.863 5.17 0.935 12 64

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
12123767 2002 2 1 0 1 2:1 AV block
15840476 2005 1 1 0 0
25904541 2015 1 1 0 0
27566755 2016 1 1 0 0
30059973 2018 1 1 0 0
Literature, cohort, and gnomAD – 1 0 1 0 –
Variant features alone – 15 12 2 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)
12123767 2002 HEK-tSA201 10 7 9 4000
15840476 2005
12123759 2002
25904541 2015
27566755 2016
30059973 2018
12454206 2003 HEK 20

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 M1766L.
Neighbour residue Distance (Å) Observed variants
403 14
1328 11 V1328M,
1659 11
1773 11
1765 6
1653 12
1757 11
1472 9 p.N1472del, N1472S,
1315 14
1771 10 I1771T,
1756 14 I1756V,
1314 14 c.3940_3941delCT,
1320 10 M1320I, M1320I, M1320I,
1764 6 V1764F, c.5290delG,
1666 14
409 15 L409P, L409V,
1333 13
1656 10
1477 12 K1477N, K1477N,
1471 12
935 15 L935P,
1762 6 I1762M, p.I1762del,
1470 9
1464 14 c.4389_4396delCCTCTTTA, L1464P,
1466 9 c.4396_4397insG,
1767 7 Y1767C,
1660 6 I1660S, I1660V,
1654 15
1329 11 G1329S,
1769 6
402 11 F402L, F402L, F402L,
1766 0 M1766V, M1766L, M1766T, M1766L,
1319 12 G1319V,
1768 7 I1768V,
1774 13 N1774D, c.5321_5324dupACTT,
1473 6 F1473C, F1473S,
1334 11 I1334V,
1468 10 V1468F, V1468A,
1663 9
1462 15
1657 9
1474 13
1759 9 S1759C,
1662 12
1324 9
1327 7
1709 14 T1709M, p.T1709del, T1709R,
1758 10 p.I1758del, I1758V,
1755 14
1330 9 A1330P, A1330D, A1330T,
1772 11 L1772V,
1323 7 V1323G,
1770 7 I1770V,
1708 13 T1708I,
1322 10 c.3963+2T>C, c.3963+4A>G,
1326 7 A1326S,
1763 4 V1763L, V1763L, V1763M,
1332 14 P1332L, P1332Q,
1465 11 p.F1465_L1480dup,
1760 11
1467 11
1476 11 Q1476R, Q1476X,
1661 10 G1661R, G1661R, G1661E,
1331 11 I1331V,
1761 10 L1761F, c.5280delG, L1761H,
1655 14
1475 14 Q1475L, p.Q1475NfsX6,
1469 6 I1469V,
406 12 N406K, N406S, N406K,
1325 11 N1325S,
398 13
1667 12 V1667I,
1664 10
1463 14 N1463Y,
1658 13