SCN5A Variant D1689N Detail

We estimate the penetrance of LQTS for SCN5A D1689N around 10% and the Brugada syndrome penetrance around 17%. SCN5A D1689N was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D1689N is present in 1 alleles in gnomAD. D1689N has been functionally characterized in 0 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 (1 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 D1689N around 10% (0/11) and the Brugada syndrome penetrance around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.34 0.999 4.99 0.669 28 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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 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.

D1689N has 56 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 8 c.998+5G>A, c.998+1G>A,
1702 11
326 11
387 13
385 14 A385T,
1715 11
1687 6
330 15 S330F,
1698 13 A1698T,
334 10 c.999-424_1338+81del,
332 10 A332T,
1681 14 Y1681F, c.5040_5042delTTAinsC,
1694 11
327 13
1706 12 Q1706H,
1695 11 Q1695X,
376 12 R376H, R376C,
384 13 S384T,
1716 11 p.L1716SfsX71,
1688 5
1684 6 W1684R,
329 15
1692 5
386 13 G386R, G386E,
1693 8
378 12
1699 10
331 12
1712 13 G1712S, G1712C,
379 7
1680 15 A1680T, A1680P,
1703 10
1719 11
335 13 C335R, C335S,
325 11 L325R,
1690 5 c.5068_5070delGA, D1690N,
324 9
383 7
280 14 C280Y,
323 13
1683 12
382 10
1718 14 S1718R,
1696 13
1689 0 D1689N,
1700 13
1682 12
336 13 P336L,
381 13 c.1140+1G>A, c.1141-3C>A,
1686 9
375 12
1691 5
380 11
1720 14 c.5157delC,
377 15
1685 9