SCN5A Variant V412D Detail

We estimate the penetrance of LQTS for SCN5A V412D around 20% and the Brugada syndrome penetrance around 40%. SCN5A V412D was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. V412D is not present in gnomAD. V412D 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 V412D around 20% (1/11) and the Brugada syndrome penetrance around 40% (4/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.87 1 -6.23 0.987 43 34
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
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
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)
29325976 2018

V412D has 70 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
414 6 M414V,
939 11 L939F,
404 13 L404Q, L404V,
937 11
1773 14
842 12
249 9 K249X,
247 9 V247L,
240 13 V240M,
254 13
1771 13 I1771T,
418 10 E418K,
926 11
250 8
409 5 L409V, L409P,
928 9 L928P,
925 12 I925F,
417 10
934 11
933 6
246 5
935 9 L935P,
1779 13 T1779M,
412 0 V412D,
924 12 V924I,
1470 14
927 11 N927S, N927K,
1466 14 c.4396_4397insG,
245 9 Q245K,
1776 12
845 15 c.2533delG,
244 11
1769 14
415 6 A415T,
1768 13 I1768V,
940 12 S940N,
405 11
248 12
938 12
241 11
420 12
419 11 Q419X,
930 9 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1772 10 L1772V,
239 11 I239V, I239V ,
251 13
410 6 A410V,
1780 15 E1780G,
242 8 A242D,
929 6
416 7 Y416C,
413 4 A413T, A413E,
408 7
253 12
407 9
846 15 L846R,
936 7
238 13
1467 14
1775 10 F1775V, p.F1775LfsX15,
923 15
421 14
406 10 N406K, N406S,
252 14
411 4 V411M,
243 8
932 6
931 10
1646 14
1463 14 N1463Y,