SCN5A Variant V405A Detail

We estimate the penetrance of LQTS for SCN5A V405A around 43% and the Brugada syndrome penetrance around 15%. SCN5A V405A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V405A is not present in gnomAD. V405A has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A V405A around 43% (2/10) and the Brugada syndrome penetrance around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.932 12 57
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 12 2 1 - -
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.

V405A 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
403 8
414 15 M414V,
896 14 C896S,
404 5 L404Q, L404V,
895 14 L895F,
1765 11
396 12 V396A, V396L,
247 14 V247L,
1653 15
254 11
372 13
1771 9 I1771T,
401 5 S401P,
926 12
1764 11 c.5290delG, V1764F,
371 9 Q371E,
250 11
409 7 L409V, L409P,
928 7 L928P,
925 14 I925F,
1650 12 L1650F,
260 13
366 11
365 14
933 13
258 14 V258A,
246 14
935 11 L935P,
412 11 V412D,
897 12 G897E, G897R,
924 11 V924I,
1470 15
927 9 N927K, N927S,
1466 13 c.4396_4397insG,
369 7 M369K,
1767 10 Y1767C,
1769 12
402 7 F402L,
1649 15 A1649V,
1768 8 I1768V,
256 12
399 12
397 10 I397F, I397T, I397V,
405 0
1657 14
261 13
920 14
1709 13 p.T1709del, T1709R, T1709M,
930 13 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1772 10 L1772V,
251 15
410 9 A410V,
1770 13 I1770V,
929 11
413 13 A413T, A413E,
408 5
374 15 W374G,
253 11
407 7
367 14 R367H, R367C, R367L,
936 14
1760 14
1775 13 F1775V, p.F1775LfsX15,
370 8 T370M,
923 11
406 4 N406K, N406S,
368 12
899 14
1710 15 S1710L,
411 11 V411M,
932 8
398 12
1647 15
257 10
400 8 G400A, G400R, G400E,
931 11
1646 13
1463 13 N1463Y,