SCN5A Variant A1698T Detail

We estimate the penetrance of LQTS for SCN5A A1698T around 3% and the Brugada syndrome penetrance around 24%. SCN5A A1698T was found in a total of 4 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. A1698T is present in 3 alleles in gnomAD. A1698T has been functionally characterized in 2 papers. This residue is located in a Mild_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 (2 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 A1698T around 3% (0/14) and the Brugada syndrome penetrance around 24% (3/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.43 1 -1.6 0.872 25 0
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
20129283 2010 1 0 1 0
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 4 3 0 1 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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)
20129283 2010
29325976 2018

A1698T has 65 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
333 13 c.998+1G>A, c.998+5G>A,
1702 6
387 6
385 14 A385T,
391 13
330 11 S330F,
388 10 I388S,
1698 0 A1698T,
1220 13 G1220E,
1673 11
1675 13
1666 15
332 12 A332T,
1707 14
1694 9
1704 10 L1704H,
1226 11
1706 12 Q1706H,
1695 9 Q1695X,
1716 15 p.L1716SfsX71,
1688 14
1669 11
1671 15
329 14
1221 14 A1221V,
1668 10 M1668T,
1676 9 M1676T, M1676I,
1692 9
386 11 G386E, G386R,
1219 15 S1219N,
1672 9 S1672Y,
1693 8
378 12
1699 4
331 8
1665 12
379 13
1680 14 A1680P, A1680T,
1703 8
1701 5 M1701I,
1228 10 Y1228H, Y1228C, Y1228F,
1690 13 D1690N, c.5068_5070delGA,
1223 9 c.3667delG,
1697 4
389 13 Y389X, Y389H,
1222 14 p.L1222LfsX7, L1222R,
1227 11
393 14
390 9
394 14
383 14
1708 15 T1708I,
382 11
1696 5
1705 10
1689 13 D1689N,
1700 5
1677 15
1224 10
1670 14
381 15 c.1141-3C>A, c.1140+1G>A,
1225 14 E1225K, G1225K,
1691 9
1679 14
1667 15 V1667I,