SCN5A Variant p.T1709del Detail

We estimate the penetrance of LQTS for SCN5A p.T1709del around 3% and the Brugada syndrome penetrance around 54%. SCN5A p.T1709del was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. p.T1709del is not present in gnomAD. p.T1709del 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 p.T1709del around 3% (0/11) and the Brugada syndrome penetrance around 54% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 73 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
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)
20129283 2010

p.T1709del has 81 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 15
1702 12
896 15 C896S,
1417 10
1765 11
396 12 V396A, V396L,
1757 13
1715 14
372 11
401 10 S401P,
1756 10 I1756V,
1764 8 V1764F, c.5290delG,
371 6 Q371E,
1711 5 c.5131delG,
1754 15
1707 7
1704 9 L1704H,
1706 7 Q1706H,
1716 12 p.L1716SfsX71,
1714 14 D1714G,
376 14 R376H, R376C,
1671 15
897 13 G897E, G897R,
1762 13 p.I1762del, I1762M,
1668 11 M1668T,
1692 15
369 12 M369K,
1753 15 T1753A,
1767 12 Y1767C,
1660 14 I1660V, I1660S,
378 11
1418 12
402 9 F402L,
1766 14 M1766T, M1766V, M1766L,
1665 15
373 10
1768 13 I1768V,
1712 9 G1712S, G1712C,
379 13
1703 11
898 13
1663 15
399 14
397 8 I397F, I397T, I397V,
405 13
1462 14
1759 8 S1759C,
1709 0 T1709M, p.T1709del, T1709R,
1701 13 M1701I,
1420 15 G1420P, G1420D, G1420R, G1420V,
1758 13 I1758V, p.I1758del,
1755 10
395 15
393 11
1713 8
390 14
394 11
1708 4 T1708I,
374 7 W374G,
1705 8
1700 15
1717 15 L1717P,
367 13 R367H, R367C, R367L,
1763 11 V1763L, V1763M,
1416 14 A1416E, c.4245+1G>A, c.4245+1G>C, c.4245+2T>A, A1416G,
1760 7
370 11 T370M,
1752 12
1661 13 G1661E, G1661R,
1761 11 c.5280delG, L1761H, L1761F,
375 10
406 14 N406S, N406K,
368 10
1710 4 S1710L,
377 13
398 11
400 13 G400R, G400A, G400E,
1419 10 K1419E,
1667 13 V1667I,
1414 14 Q1414H,
1664 10