SCN5A Variant N420D Detail

We estimate the penetrance of LQTS for SCN5A N420D around 15% and the Brugada syndrome penetrance around 13%. SCN5A N420D was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. N420D is not present in gnomAD. N420D has been functionally characterized in 0 papers. This residue is located in a Non_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 N420D around 15% (0/10) and the Brugada syndrome penetrance around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.83 9 16
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.

N420D has 45 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 11 M414V,
939 11 L939F,
937 9
839 14 L839P,
842 13
943 13 S943N,
240 12 V240M,
418 8 E418K,
237 11
234 15 P234S,
417 5
934 14
933 11
246 13
935 14 L935P,
412 12 V412D,
245 13 Q245K,
244 14
415 9 A415T,
940 7 S940N,
420 0
938 13
241 10
235 11 c.703+1G>A, c.704-1G>C, G235R,
942 14
419 5 Q419X,
423 6
834 14 N834D,
837 13
239 10 I239V , I239V,
1780 15 E1780G,
242 9 A242D,
416 5 Y416C,
413 10 A413T, A413E,
841 13 p.N841TfsX2, N841K,
236 13
941 10 S941N, S941F,
936 10
238 6
838 10
422 6
421 5
411 14 V411M,
243 13
835 13 S835A, S835L,