SCN5A Variant S354R Detail

We estimate the penetrance of LQTS for SCN5A S354R around 12% and the Brugada syndrome penetrance around 49%. SCN5A S354R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S354R is not present in gnomAD. S354R 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 (4 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 S354R around 12% (0/10) and the Brugada syndrome penetrance around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.982 72 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 11 0 4 - -
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.

S354R has 68 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 8
277 7
271 12 L271V,
266 13 L266H,
276 6 L276P, L276Q,
363 9
348 7 P348A,
270 12 Q270K,
360 7
279 13
385 13 A385T,
355 5 F355C, F355I,
1549 11
278 11 H278R, H278D,
356 5 D356N,
361 7
904 11 W904X,
366 14
343 12
365 11
376 12 R376H, R376C,
384 12 S384T,
354 0
1546 15 M1546T,
378 15
349 10 D349N,
373 15
267 13
379 15
1550 10
357 7
272 8
274 7 G274C,
362 12
273 9
325 12 L325R,
900 13
392 13
269 9
389 15 Y389X, Y389H,
345 11
393 14
275 9 N275K,
264 15
912 14 Q912R,
323 14
347 6
382 14
1548 14 G1548K, E1548K,
351 7 G351V, G351S, G351C, G351D,
265 11 A265V,
350 11 H350Q,
358 11
903 14 p.M903CfsX29,
367 11 R367C, R367L, R367H,
1551 14 D1551Y, D1551N,
346 10 E346K, E346X, E346G, E346D,
359 9 A359T, p.A359PfsX12,
344 12 A344S,
381 10 c.1140+1G>A, c.1141-3C>A,
322 15
352 8 Y352C,
368 13
380 10
268 9 G268S,
377 9
353 4 T353I,
907 14