SCN5A Variant T334A Detail

We estimate the penetrance of LQTS for SCN5A T334A around 18% and the Brugada syndrome penetrance around 36%. SCN5A T334A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T334A is not present in gnomAD. T334A 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 (3 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 T334A around 18% (0/10) and the Brugada syndrome penetrance around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.28 55 23
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 0 3 - -
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.

T334A has 44 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 7
333 3 c.998+1G>A, c.998+5G>A,
326 5
276 15 L276P, L276Q,
387 12
279 13
385 10 A385T,
338 12
330 9 S330F,
278 11 H278R, H278D,
388 15 I388S,
334 0 c.999-424_1338+81del,
332 5 A332T,
327 5
339 10
1688 15
384 9 S384T,
1684 14 W1684R,
329 8
1692 12
386 11 G386R, G386E,
340 12 R340Q, R340W,
1693 13
1699 13
331 8
379 13
341 9 C341Y,
335 4 C335S, C335R,
325 9 L325R,
1690 9 c.5068_5070delGA, D1690N,
324 10
275 14 N275K,
383 7
280 9 C280Y,
323 13
382 11
337 11
1689 10 D1689N,
342 13
336 7 P336L,
381 13 c.1140+1G>A, c.1141-3C>A,
1691 8
380 13
281 13 V281M,