SCN5A Variant M1766V Detail

We estimate the penetrance of LQTS for SCN5A M1766V around 83% and the Brugada syndrome penetrance around 6%. SCN5A M1766V was found in a total of 10 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 10 had LQTS. M1766V is not present in gnomAD. M1766V has been functionally characterized in 2 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A M1766V around 83% (12/20) and the Brugada syndrome penetrance around 6% (1/20).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.68 0.997 1.76 0.971 12 64
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
27566755 2016 10 10 0 0
LITERATURE, COHORT, AND GNOMAD: - 10 0 10 0 -
VARIANT FEATURES ALONE: - 15 12 2 1 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
27566755 2016
29017927 2017

M1766V has 75 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
403 14
1328 11 V1328M,
1659 11
1773 11
1765 6
1653 12
1757 11
1472 9 N1472S, p.N1472del,
1315 14
1771 10 I1771T,
1756 14 I1756V,
1314 14 c.3940_3941delCT,
1320 10 M1320I,
1764 6 V1764F, c.5290delG,
1666 14
409 15 L409V, L409P,
1333 13
1656 10
1477 12 K1477N,
1471 12
935 15 L935P,
1762 6 p.I1762del, I1762M,
1470 9
1464 14 L1464P, c.4389_4396delCCTCTTTA,
1466 9 c.4396_4397insG,
1767 7 Y1767C,
1660 6 I1660S, I1660V,
1654 15
1329 11 G1329S,
1769 6
402 11 F402L,
1766 0 M1766V, M1766T, M1766L,
1319 12 G1319V,
1768 7 I1768V,
1774 13 N1774D, c.5321_5324dupACTT,
1473 6 F1473C, F1473S,
1334 11 I1334V,
1468 10 V1468A, V1468F,
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 A1330D, A1330P, 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, V1763M,
1332 14 P1332Q, P1332L,
1465 11 p.F1465_L1480dup,
1760 11
1467 11
1476 11 Q1476R, Q1476X,
1661 10 G1661E, G1661R,
1331 11 I1331V,
1761 10 L1761H, L1761F, c.5280delG,
1655 14
1475 14 Q1475L, p.Q1475NfsX6,
1469 6 I1469V,
406 12 N406K, N406S,
1325 11 N1325S,
398 13
1667 12 V1667I,
1664 10
1463 14 N1463Y,
1658 13