SCN5A Variant S330F Detail

We estimate the penetrance of LQTS for SCN5A S330F around 21% and the Brugada syndrome penetrance around 13%. SCN5A S330F was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S330F is present in 1 alleles in gnomAD. S330F has been functionally characterized in 0 papers. This residue is located in a 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A S330F around 21% (1/11) and the Brugada syndrome penetrance around 13% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.29 0.966 -1.17 0.673 14 26
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.

S330F has 37 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
328 8
333 8 c.998+5G>A, c.998+1G>A,
1702 13
326 12
387 7
385 9 A385T,
391 15
330 0 S330F,
278 14 H278D, H278R,
388 8 I388S,
1698 11 A1698T,
334 9 c.999-424_1338+81del,
332 6 A332T,
327 10
384 11 S384T,
329 4
1692 13
386 8 G386R, G386E,
1693 14
1699 11
331 4
341 14 C341Y,
335 12 C335R, C335S,
325 15 L325R,
1228 13 Y1228H, Y1228F, Y1228C,
1690 14 D1690N, c.5068_5070delGA,
1697 13
389 11 Y389H, Y389X,
390 13
275 15 N275K,
383 12
1614 15
382 10
1696 13
1689 15 D1689N,
381 13 c.1140+1G>A, c.1141-3C>A,
1691 10