SCN5A Variant C341F Detail

We estimate the penetrance of LQTS for SCN5A C341F around 50% and the Brugada syndrome penetrance around 12%. SCN5A C341F was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. C341F is not present in gnomAD. C341F 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A C341F around 50% (2/10) and the Brugada syndrome penetrance around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.938 7 66
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 12 2 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.

C341F 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
328 6
333 11 c.998+1G>A, c.998+5G>A,
277 11
326 6
276 12 L276P, L276Q,
348 15 P348A,
279 8
385 11 A385T,
338 11
330 14 S330F,
278 5 H278R, H278D,
334 9 c.999-424_1338+81del,
332 11 A332T,
343 8
327 5
339 10
384 8 S384T,
329 10
282 12 R282H, R282C,
386 14 G386E, G386R,
340 6 R340Q, R340W,
283 11
272 15
341 0 C341Y,
274 11 G274C,
335 8 C335S, C335R,
319 15 G319C, G319R, G319S,
325 9 L325R,
324 12
321 14 S321Y,
345 12
275 10 N275K,
383 11
280 6 C280Y,
323 11
347 15
382 15
337 13
320 13 T320N,
342 4
336 10 P336L,
344 9 A344S,
381 14 c.1141-3C>A, c.1140+1G>A,
380 14
281 7 V281M,