SCN5A Variant A415D Detail

We estimate the penetrance of LQTS for SCN5A A415D around 13% and the Brugada syndrome penetrance around 14%. SCN5A A415D was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A415D is not present in gnomAD. A415D has been functionally characterized in 0 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 (1 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 A415D around 13% (0/10) 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 0.926 10 14
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 14 0 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.

A415D has 61 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 4 M414V,
939 12 L939F,
937 12
1778 14
1773 15
842 14
249 7 K249X,
247 10 V247L,
240 11 V240M,
1777 15 V1777M, V1777L,
418 5 E418K,
250 11
409 10 L409P, L409V,
237 13
928 14 L928P,
417 7
934 14
933 9
246 6
935 13 L935P,
1779 11 T1779M,
412 6 V412D,
245 6 Q245K,
1776 11
244 10
415 0 A415T,
940 12 S940N,
420 9
248 11
938 15
241 8
419 7 Q419X,
930 12 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
423 12
1772 12 L1772V,
239 10 I239V, I239V ,
251 14
410 8 A410V,
1780 12 E1780G,
242 6 A242D,
929 11
416 6 Y416C,
413 5 A413T, A413E,
408 11
253 14
407 13
1783 14
936 9
238 10
422 10
1775 11 p.F1775LfsX15, F1775V,
1642 15 G1642E,
421 10
406 15 N406K, N406S,
252 15
411 6 V411M,
243 9
932 11
931 15
1646 15
1782 14