SCN5A Variant K387N Detail

We estimate the penetrance of LQTS for SCN5A K387N around 6% and the Brugada syndrome penetrance around 34%. SCN5A K387N was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. K387N is not present in gnomAD. K387N 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 K387N around 6% (0/10) and the Brugada syndrome penetrance around 34% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.783 47 4
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: - 0 0 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.

K387N has 53 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
328 12
333 10 c.998+1G>A, c.998+5G>A,
271 15 L271V,
1702 7
326 14
387 0
385 8 A385T,
391 10
330 7 S330F,
388 5 I388S,
1698 6 A1698T,
334 12 c.999-424_1338+81del,
332 7 A332T,
1694 14
1704 14 L1704H,
327 12
1706 14 Q1706H,
1695 14 Q1695X,
384 11 S384T,
329 8
1668 14 M1668T,
1692 10
386 5 G386R, G386E,
1672 15 S1672Y,
1693 12
378 10
1699 8
331 5
379 12
1703 12
272 14
1701 9 M1701I,
325 15 L325R,
1228 14 Y1228H, Y1228C, Y1228F,
1690 14 c.5068_5070delGA, D1690N,
1223 15 c.3667delG,
392 13
1697 9
389 8 Y389H, Y389X,
393 11
390 7
394 12
275 15 N275K,
383 11
382 7
1696 10
1705 11
1689 13 D1689N,
1700 11
1224 14
381 10 c.1141-3C>A, c.1140+1G>A,
1691 8
380 14