SCN5A Variant c.1140+1G>A Detail

We estimate the penetrance of LQTS for SCN5A c.1140+1G>A around 20% and the Brugada syndrome penetrance around 48%. SCN5A c.1140+1G>A was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. c.1140+1G>A is not present in gnomAD. c.1140+1G>A has been functionally characterized in 1 papers. This residue is located in a 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 (4 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A c.1140+1G>A around 20% (1/11) and the Brugada syndrome penetrance around 48% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 62 30
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
24915601 2014 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 10 1 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)
24915601 2014

c.1140+1G>A has 78 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 11 c.998+1G>A, c.998+5G>A,
364 12
277 12
271 10 L271V,
1702 11
326 11
276 6 L276P, L276Q,
387 10
348 11 P348A,
270 15 Q270K,
279 13
396 13 V396A, V396L,
385 6 A385T,
355 9 F355C, F355I,
1687 15
391 12
330 13 S330F,
278 10 H278R, H278D,
388 10 I388S,
1698 15 A1698T,
356 14 D356N,
334 13 c.999-424_1338+81del,
361 13
332 9 A332T,
343 14
365 13
327 10
1706 12 Q1706H,
376 10 R376H, R376C,
384 6 S384T,
354 10
329 11
1692 11
386 6 G386R, G386E,
378 6
1699 14
331 13
349 13 D349N,
373 14
267 13
379 7
1703 14
272 7
341 14 C341Y,
397 14 I397T, I397F, I397V,
274 10 G274C,
273 13
325 8 L325R,
392 9
324 12
389 7 Y389X, Y389H,
269 14
395 14
393 8
394 13
390 10
275 8 N275K,
383 8
280 15 C280Y,
264 15
323 14
347 12
382 4
351 15 G351S, G351C, G351V, G351D,
265 14 A265V,
374 10 W374G,
1705 13
1689 13 D1689N,
367 12 R367C, R367H, R367L,
381 0 c.1140+1G>A, c.1141-3C>A,
375 11
1691 11
368 11
380 5
268 10 G268S,
377 6
353 10 T353I,