SCN5A Variant G400A Detail

We estimate the penetrance of LQTS for SCN5A G400A around 10% and the Brugada syndrome penetrance around 19%. SCN5A G400A was found in a total of 1 carriers in 3 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. G400A is present in 1 alleles in gnomAD. G400A has been functionally characterized in 3 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 G400A around 10% (0/11) and the Brugada syndrome penetrance around 19% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.89 1 -2.07 0.957 19 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
17675083 2007 1 0 0 1 Arrymthmic story during AMI
17993325 2007 1 0 0 1 AMI
19345130 2009 1 0 0 1 VF, arrhythmic storm
LITERATURE, COHORT, AND GNOMAD: - 1 1 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.

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)
17675083 2007 tsA201 25 1.32 -6.39 9
17993325 2007 tsA201 70 -6.4
19345130 2009

G400A has 69 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
403 5
364 13
404 5 L404V, L404Q,
396 6 V396A, V396L,
1653 13
391 14
254 13
372 14
1771 11 I1771T,
401 4 S401P,
1634 15 L1634P,
1764 13 V1764F, c.5290delG,
371 9 Q371E,
409 14 L409V, L409P,
928 14 L928P,
1650 11 L1650F,
260 8
366 11
365 10
258 12 V258A,
369 5 M369K,
1767 10 Y1767C,
1660 14 I1660V, I1660S,
1654 12
402 6 F402L,
1649 14 A1649V,
1768 12 I1768V,
267 13
262 13 S262G,
256 10
399 5
397 6 I397F, I397T, I397V,
405 8
1657 11
362 14
261 9
1709 13 T1709M, p.T1709del, T1709R,
392 11
255 15
1772 15 L1772V,
395 8
393 11
394 10
410 14 A410V,
1770 14 I1770V,
1658 13
264 8
1651 14
1708 15 T1708I,
259 12
265 13 A265V,
408 11
374 13 W374G,
253 12
1705 14
407 10
367 13 R367H, R367C, R367L,
263 11 V263I,
370 10 T370M,
1661 14 G1661E, G1661R,
1631 15 G1631D,
406 9 N406S, N406K,
368 9
398 7
1647 13
257 9
400 0 G400R, G400A, G400E,
1646 14
1664 15