SCN5A Variant I1660S Detail

We estimate the penetrance of LQTS for SCN5A I1660S around 4% and the Brugada syndrome penetrance around 48%. SCN5A I1660S was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. I1660S is not present in gnomAD. I1660S has been functionally characterized in 1 papers. This residue is located in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (4 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A I1660S around 4% (0/11) and the Brugada syndrome penetrance around 48% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.48 1 -4.96 0.949 60 6
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
25650408 2015 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 4 - -
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)
25650408 2015

I1660S has 73 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 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,
1764 8 V1764F, c.5290delG,
1666 11
1650 14 L1650F,
1656 6
1477 14 K1477N,
1762 10 I1762M, p.I1762del,
1470 14
1668 12 M1668T,
1466 14 c.4396_4397insG,
1767 6 Y1767C,
1313 14
1660 0 I1660S, I1660V,
1654 11
1769 10
402 10 F402L,
1766 6 M1766V, M1766T, M1766L,
1319 9 G1319V,
1665 11
1768 10 I1768V,
1774 14 N1774D, c.5321_5324dupACTT,
1473 11 F1473C, F1473S,
1663 5
399 12
397 14 I397F, I397T, I397V,
1657 6
1759 10 S1759C,
1662 7
1324 10
1317 11 F1317C,
1327 10
1709 14 p.T1709del, T1709R, T1709M,
1758 12 p.I1758del, I1758V,
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 V1763L, V1763M,
1311 13 L1311P,
1760 14
1476 14 Q1476X, Q1476R,
1670 15
1661 4 G1661R, G1661E,
1761 14 c.5280delG, L1761F, L1761H,
1655 9
1469 12 I1469V,
406 13 N406K, N406S,
1325 13 N1325S,
398 9
400 14 G400E, G400R, G400A,
1667 10 V1667I,
1664 6
1658 8