SCN5A Variant Q419L Detail

We estimate the penetrance of LQTS for SCN5A Q419L around 12% and the Brugada syndrome penetrance around 13%. SCN5A Q419L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q419L is not present in gnomAD. Q419L 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 Q419L around 12% (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 0.786 10 12
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.

Q419L has 41 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 10 M414V,
939 15 L939F,
937 12
842 14
249 12 K249X,
247 14 V247L,
240 9 V240M,
418 5 E418K,
237 8
234 15 P234S,
417 7
933 11
246 11
412 11 V412D,
245 8 Q245K,
244 10
415 7 A415T,
940 12 S940N,
420 5
248 13
241 6
235 10 c.704-1G>C, c.703+1G>A, G235R,
419 0 Q419X,
423 6
837 15
239 8 I239V , I239V,
410 15 A410V,
242 6 A242D,
929 15
416 6 Y416C,
413 11 A413E, A413T,
841 13 N841K, p.N841TfsX2,
236 11
941 15 S941N, S941F,
936 12
238 6
838 13
422 5
421 7
411 13 V411M,
243 10