SCN5A Variant c.998+5G>A Detail

We estimate the penetrance of LQTS for SCN5A c.998+5G>A around 41% and the Brugada syndrome penetrance around 31%. SCN5A c.998+5G>A was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. c.998+5G>A is not present in gnomAD. c.998+5G>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 (3 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.998+5G>A around 41% (2/11) and the Brugada syndrome penetrance around 31% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 48 37
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
23631430 2013 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 11 1 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.

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)
23631430 2013

c.998+5G>A has 51 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 0 c.998+5G>A, c.998+1G>A,
1702 12
326 6
276 14 L276Q, L276P,
387 10
279 14
385 9 A385T,
338 15
1687 13
330 8 S330F,
278 11 H278D, H278R,
388 13 I388S,
1698 13 A1698T,
334 3 c.999-424_1338+81del,
332 3 A332T,
327 6
339 13
1695 13 Q1695X,
384 8 S384T,
1688 13
1684 13 W1684R,
329 7
1692 9
386 8 G386E, G386R,
1693 11
378 13
1699 10
331 6
379 11
1703 14
341 11 C341Y,
335 7 C335S, C335R,
325 9 L325R,
1690 8 D1690N, c.5068_5070delGA,
324 10
389 13 Y389H, Y389X,
390 15
275 14 N275K,
383 5
280 11 C280Y,
323 13
382 8
337 14
1696 13
1689 8 D1689N,
342 15
336 10 P336L,
381 11 c.1140+1G>A, c.1141-3C>A,
1691 5
380 11