SCN5A Variant A364S Detail

We estimate the penetrance of LQTS for SCN5A A364S around 10% and the Brugada syndrome penetrance around 38%. SCN5A A364S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A364S is not present in gnomAD. A364S 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 A364S around 10% (0/10) and the Brugada syndrome penetrance around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.349 58 12
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.

A364S has 78 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
364 0
277 15
271 13 L271V,
266 12 L266H,
919 15
901 14 E901K, S901L,
276 11 L276Q, L276P,
363 4
348 12 P348A,
270 15 Q270K,
360 8
396 10 V396L, V396A,
355 6 F355I, F355C,
372 9
401 13 S401P,
356 11 D356N,
371 11 Q371E,
361 5
904 10 W904X,
260 14
366 7
365 5
376 12 R376H, R376C,
258 14 V258A,
354 8
897 14 G897E, G897R,
1546 15 M1546T,
369 9 M369K,
378 13
902 15
349 12 D349N,
373 11
267 12
379 15
262 12 S262G,
357 11
898 15
272 11
397 12 I397V, I397F, I397T,
274 14 G274C,
362 7
261 9
273 14
920 12
900 9
392 11
269 11
395 14
393 11
917 15 L917V, L917R,
916 12
275 14 N275K,
264 11
912 14 Q912R,
347 12
351 12 G351S, G351D, G351C, G351V,
265 8 A265V,
374 10 W374G,
350 13 H350Q,
358 10
903 11 p.M903CfsX29,
367 5 R367H, R367L, R367C,
263 13 V263I,
359 9 p.A359PfsX12, A359T,
370 10 T370M,
381 12 c.1140+1G>A, c.1141-3C>A,
923 14
375 13
352 10 Y352C,
368 6
899 10
380 12
268 9 G268S,
377 7
257 14
400 13 G400E, G400A, G400R,
353 7 T353I,
907 13