SCN5A Variant R383K Detail

We estimate the penetrance of LQTS for SCN5A R383K around 12% and the Brugada syndrome penetrance around 29%. SCN5A R383K was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R383K is not present in gnomAD. R383K has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_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 R383K around 12% (0/10) and the Brugada syndrome penetrance around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.886 38 13
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 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.

R383K has 63 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 11
333 5 c.998+5G>A, c.998+1G>A,
277 14
1702 12
326 5
276 10 L276P, L276Q,
387 11
348 11 P348A,
279 11
385 8 A385T,
1687 11
330 12 S330F,
278 10 H278D, H278R,
388 13 I388S,
1698 14 A1698T,
334 7 c.999-424_1338+81del,
332 6 A332T,
327 7
1706 14 Q1706H,
339 14
376 11 R376C, R376H,
384 6 S384T,
1688 12
1684 12 W1684R,
329 10
1692 8
386 8 G386E, G386R,
1693 12
378 10
1699 12
331 10
349 14 D349N,
379 7
1703 13
272 13
341 11 C341Y,
274 14 G274C,
335 10 C335R, C335S,
325 5 L325R,
1690 10 D1690N, c.5068_5070delGA,
324 6
389 12 Y389H, Y389X,
393 14
390 14
275 12 N275K,
383 0
280 9 C280Y,
323 10
347 14
382 7
374 15 W374G,
1689 7 D1689N,
342 14
336 11 P336L,
381 8 c.1141-3C>A, c.1140+1G>A,
1686 14
322 14
375 12
1691 6
380 7
377 11
281 14 V281M,
353 14 T353I,