SCN5A Variant C335Y Detail

We estimate the penetrance of LQTS for SCN5A C335Y around 8% and the Brugada syndrome penetrance around 52%. SCN5A C335Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. C335Y is not present in gnomAD. C335Y has been functionally characterized in 0 papers. This residue is located in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (5 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 C335Y around 8% (0/10) and the Brugada syndrome penetrance around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.917 79 6
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 10 0 5 - -
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.

C335Y has 35 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 7 c.998+5G>A, c.998+1G>A,
326 5
279 12
385 13 A385T,
338 8
330 12 S330F,
278 11 H278R, H278D,
334 4 c.999-424_1338+81del,
332 9 A332T,
327 7
339 7
384 11 S384T,
284 15
329 10
282 11 R282C, R282H,
340 9 R340W, R340Q,
386 14 G386E, G386R,
331 12
283 12
341 8 C341Y,
335 0 C335R, C335S,
325 10 L325R,
1690 12 D1690N, c.5068_5070delGA,
324 11
383 10
280 7 C280Y,
323 12
382 15
337 8
1689 13 D1689N,
342 11
336 4 P336L,
1691 12
281 10 V281M,