SCN5A Variant A413V Detail

We estimate the penetrance of LQTS for SCN5A A413V around 41% and the Brugada syndrome penetrance around 14%. SCN5A A413V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A413V is not present in gnomAD. A413V has been functionally characterized in 0 papers. This residue is located in a Non_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 A413V around 41% (2/10) and the Brugada syndrome penetrance around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.932 10 54
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.

A413V has 73 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 5 M414V,
939 8 L939F,
404 15 L404V, L404Q,
937 10
1778 13
1773 11
842 14
249 10 K249X,
943 14 S943N,
247 13 V247L,
240 15 V240M,
1771 12 I1771T,
1777 13 V1777M, V1777L,
418 9 E418K,
926 15
250 12
409 6 L409P, L409V,
928 12 L928P,
417 6
934 11
933 7
1471 13
246 8
935 8 L935P,
1779 11 T1779M,
412 4 V412D,
1470 11
927 14 N927K, N927S,
1466 12 c.4396_4397insG,
245 11 Q245K,
1776 9
244 14
1769 12
415 5 A415T,
1768 12 I1768V,
940 9 S940N,
1774 13 c.5321_5324dupACTT, N1774D,
405 13
420 10
248 15
1474 14
938 11
241 12
942 14
419 11 Q419X,
930 12 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1772 8 L1772V,
239 12 I239V , I239V,
410 5 A410V,
1780 12 E1780G,
242 9 A242D,
1770 15 I1770V,
929 10
416 6 Y416C,
413 0 A413T, A413E,
408 9
253 14
941 13 S941F, S941N,
407 10
936 5
238 13
838 15
422 14
1467 12
1775 9 F1775V, p.F1775LfsX15,
421 12
406 11 N406S, N406K,
411 6 V411M,
243 11
932 8
931 12
1646 14
1463 14 N1463Y,