SCN5A Variant A385P Detail

We estimate the penetrance of LQTS for SCN5A A385P around 10% and the Brugada syndrome penetrance around 24%. SCN5A A385P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A385P is not present in gnomAD. A385P has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 A385P around 10% (0/10) and the Brugada syndrome penetrance around 24% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.874 29 9
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 13 0 2 - -
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.

A385P has 59 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 9 c.998+5G>A, c.998+1G>A,
277 13
271 9 L271V,
1702 12
326 9
276 8 L276P, L276Q,
387 8
348 14 P348A,
270 14 Q270K,
279 13
385 0 A385T,
355 12 F355I, F355C,
391 12
330 9 S330F,
278 8 H278R, H278D,
388 7 I388S,
1698 14 A1698T,
334 10 c.999-424_1338+81del,
332 6 A332T,
343 13
327 7
384 4 S384T,
354 13
329 6
1692 13
386 3 G386R, G386E,
378 10
1699 14
331 10
267 14
379 12
272 8
341 11 C341Y,
274 10 G274C,
273 13
335 13 C335S, C335R,
325 9 L325R,
392 11
324 13
389 6 Y389H, Y389X,
269 15
1620 12 T1620M, T1620K,
393 11
390 11
275 7 N275K,
383 8
280 14 C280Y,
382 6
1619 15 c.4856delC, P1619L, P1619Q,
1689 14 D1689N,
342 14
381 6 c.1141-3C>A, c.1140+1G>A,
1691 11
380 10
268 12 G268S,
377 12
1621 15
353 15 T353I,