SCN5A Variant A410V Detail

We estimate the penetrance of LQTS for SCN5A A410V around 27% and the Brugada syndrome penetrance around 10%. SCN5A A410V was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A410V is present in 1 alleles in gnomAD. A410V 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A A410V around 27% (1/11) and the Brugada syndrome penetrance around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.92 1 0.74 0.953 7 42
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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 13 1 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.

A410V has 84 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 12
414 6 M414V,
939 11 L939F,
1643 13 I1643L,
404 10 L404Q, L404V,
937 14
1778 11
1773 9
1765 14
249 10 K249X,
247 12 V247L,
1653 13
254 13
1771 8 I1771T,
401 14 S401P,
1652 14 M1652T, M1652R,
1777 11 V1777M, V1777L,
418 12 E418K,
250 9
409 4 L409V, L409P,
928 11 L928P,
1650 11 L1650F,
417 11
934 14
933 11
1471 15
246 9
935 10 L935P,
1779 9 T1779M,
412 6 V412D,
924 14 V924I,
1470 11
927 14 N927S, N927K,
1466 12 c.4396_4397insG,
245 13 Q245K,
1776 8
1767 13 Y1767C,
1648 15
1769 10
402 14 F402L,
415 8 A415T,
1649 11 A1649V,
1768 9 I1768V,
940 14 S940N,
1774 10 c.5321_5324dupACTT, N1774D,
1473 15 F1473C, F1473S,
256 14
405 9
1657 15
248 15
1474 14
938 14
419 15 Q419X,
930 14 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1772 5 L1772V,
1645 13 T1645M,
251 13
410 0 A410V,
1780 12 E1780G,
242 13 A242D,
1770 11 I1770V,
929 11
416 11 Y416C,
413 5 A413T, A413E,
408 6
253 10
407 5
936 10
1467 13
1775 5 p.F1775LfsX15, F1775V,
1642 13 G1642E,
1469 15 I1469V,
406 7 N406K, N406S,
252 13
411 4 V411M,
243 14
932 9
1647 13
257 14
400 14 G400E, G400A, G400R,
931 14
1646 9
1782 14
1463 15 N1463Y,