SCN5A Variant T1708I Detail

We estimate the penetrance of LQTS for SCN5A T1708I around 7% and the Brugada syndrome penetrance around 28%. SCN5A T1708I was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T1708I is present in 1 alleles in gnomAD. T1708I has been functionally characterized in 0 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 (3 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 T1708I around 7% (0/11) and the Brugada syndrome penetrance around 28% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.45 1 -1.15 0.895 42 5
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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
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.

T1708I has 74 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
1702 11
1417 12
1765 11
396 14 V396L, V396A,
1757 11
1715 15
372 15
1698 15 A1698T,
401 12 S401P,
1756 9 I1756V,
1764 8 c.5290delG, V1764F,
1666 13
371 10 Q371E,
1711 8 c.5131delG,
1754 12
1707 5
1694 14
1704 6 L1704H,
1706 7 Q1706H,
1716 12 p.L1716SfsX71,
1669 14
1671 11
1762 11 p.I1762del, I1762M,
1668 7 M1668T,
1692 14
1753 13 T1753A,
1672 12 S1672Y,
1767 12 Y1767C,
1660 12 I1660S, I1660V,
378 12
1699 15
402 10 F402L,
1766 13 M1766L, M1766T, M1766V,
1665 11
373 14
1768 14 I1768V,
1712 10 G1712C, G1712S,
379 15
1703 9
1663 11
399 15
397 10 I397V, I397T, I397F,
1657 15
1759 5 S1759C,
1662 14
1709 4 p.T1709del, T1709M, T1709R,
1701 10 M1701I,
1758 10 p.I1758del, I1758V,
1755 6
393 13
1713 8
390 13
394 11
1708 0 T1708I,
374 10 W374G,
1705 6
1700 12
1717 14 L1717P,
1763 9 V1763M, V1763L,
1751 12
1760 8
370 15 T370M,
1752 11
1670 13
1661 11 G1661E, G1661R,
1761 11 c.5280delG, L1761H, L1761F,
375 12
368 14
1710 7 S1710L,
398 11
400 15 G400E, G400R, G400A,
1419 13 K1419E,
1667 9 V1667I,
1664 7