SCN5A Variant H278R Detail

We estimate the penetrance of LQTS for SCN5A H278R around 3% and the Brugada syndrome penetrance around 61%. SCN5A H278R was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. H278R is not present in gnomAD. H278R 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 (5 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 H278R around 3% (0/11) and the Brugada syndrome penetrance around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.83 0.669 0.07 0.801 90 3
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
26729854 2016 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
26729854 2016

H278R has 57 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 8
333 11 c.998+5G>A, c.998+1G>A,
277 7
271 13 L271V,
326 7
276 7 L276P, L276Q,
348 11 P348A,
279 6
385 8 A385T,
355 13 F355I, F355C,
330 14 S330F,
278 0 H278R, H278D,
356 13 D356N,
334 11 c.999-424_1338+81del,
332 11 A332T,
343 6
327 6
339 14
384 5 S384T,
354 11
329 11
386 11 G386E, G386R,
340 11 R340W, R340Q,
349 15 D349N,
379 15
1550 11
272 10
341 5 C341Y,
274 6 G274C,
273 11
335 11 C335S, C335R,
325 6 L325R,
324 11
321 13 S321Y,
269 15
389 13 Y389H, Y389X,
345 10
275 5 N275K,
383 10
280 8 C280Y,
323 10
347 10
382 12
351 14 G351D, G351V, G351C, G351S,
320 13 T320N,
342 6
1551 13 D1551Y, D1551N,
346 12 E346G, E346D, E346X, E346K,
336 14 P336L,
344 7 A344S,
381 10 c.1141-3C>A, c.1140+1G>A,
322 14
380 10
268 14 G268S,
377 14
281 10 V281M,
353 13 T353I,