SCN5A Variant G386E Detail

We estimate the penetrance of LQTS for SCN5A G386E around 5% and the Brugada syndrome penetrance around 60%. SCN5A G386E was found in a total of 2 carriers in 1 papers and/or in gnomAD: 2 had Brugada syndrome, 0 had LQTS. G386E is not present in gnomAD. G386E 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 G386E around 5% (0/12) and the Brugada syndrome penetrance around 60% (7/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.85 1 -3.75 0.971 76 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
20129283 2010 2 0 2 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 0 2 -
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)
20129283 2010

G386E has 58 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 9
333 8 c.998+5G>A, c.998+1G>A,
271 11 L271V,
1702 9
326 11
276 11 L276Q, L276P,
387 5
385 3 A385T,
355 14 F355C, F355I,
391 10
330 8 S330F,
278 11 H278R, H278D,
388 5 I388S,
1698 11 A1698T,
334 11 c.999-424_1338+81del,
332 5 A332T,
327 9
1706 14 Q1706H,
384 6 S384T,
329 6
1692 10
386 0 G386R, G386E,
1693 14
378 9
1699 11
331 8
379 10
1703 14
272 9
341 14 C341Y,
274 13 G274C,
335 14 C335R, C335S,
1701 13 M1701I,
325 11 L325R,
1690 15 D1690N, c.5068_5070delGA,
392 11
324 14
1697 14
389 5 Y389H, Y389X,
1620 13 T1620M, T1620K,
395 15
393 10
394 13
390 8
275 10 N275K,
383 8
382 4
374 14 W374G,
1696 14
1705 13
1689 13 D1689N,
1700 14
381 6 c.1141-3C>A, c.1140+1G>A,
375 15
1691 9
380 11
268 13 G268S,
377 12