SCN5A Variant p.I1762del Detail

We estimate the penetrance of LQTS for SCN5A p.I1762del around 63% and the Brugada syndrome penetrance around 14%. SCN5A p.I1762del was found in a total of 1 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. p.I1762del is not present in gnomAD. p.I1762del 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 p.I1762del around 63% (3/11) and the Brugada syndrome penetrance around 14% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 13 75
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
20541041 2010 1 1 0 0
27566755 2016 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 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)
20541041 2010
27566755 2016

p.I1762del has 68 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
1328 11 V1328M,
1417 14
1765 6
1757 6
1472 11 N1472S, p.N1472del,
1756 9 I1756V,
1461 14 T1461S,
1320 14 M1320I,
1764 7 V1764F, c.5290delG,
1666 14
1333 11
1754 11
1707 14
1471 14
1671 13
1762 0 p.I1762del, I1762M,
1470 12
1464 12 L1464P, c.4389_4396delCCTCTTTA,
1668 14 M1668T,
1466 9 c.4396_4397insG,
1753 13 T1753A,
1767 11 Y1767C,
1660 10 I1660S, I1660V,
1329 11 G1329S,
1769 11
402 14 F402L,
1766 6 M1766V, M1766T, M1766L,
1768 10 I1768V,
1473 11 F1473C, F1473S,
1334 7 I1334V,
1341 14
1468 10 V1468A, V1468F,
1663 10
1657 14
1462 11
1759 6 S1759C,
1324 11
1327 7
1709 13 T1709M, p.T1709del, T1709R,
1758 5 p.I1758del, I1758V,
1755 10
1330 8 A1330D, A1330P, A1330T,
1713 14
1323 11 V1323G,
1338 11 L1338V,
1770 13 I1770V,
1708 11 T1708I,
1322 14 c.3963+2T>C, c.3963+4A>G,
1337 11
1326 10 A1326S,
1763 5 V1763L, V1763M,
1332 12 P1332Q, P1332L,
1465 7 p.F1465_L1480dup,
1760 8
1467 11
1752 15
1661 13 G1661E, G1661R,
1331 8 I1331V,
1761 5 L1761H, L1761F, c.5280delG,
1469 7 I1469V,
406 15 N406K, N406S,
1336 14
1710 13 S1710L,
1325 14 N1325S,
1335 12 M1335R,
1667 11 V1667I,
1664 11
1463 12 N1463Y,