SCN5A Variant S357A Detail

We estimate the penetrance of LQTS for SCN5A S357A around 9% and the Brugada syndrome penetrance around 38%. SCN5A S357A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S357A is not present in gnomAD. S357A 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 (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 S357A around 9% (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 0.663 56 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 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.

S357A has 54 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 11
277 11
271 13 L271V,
266 10 L266H,
276 12 L276P, L276Q,
363 10
1544 14 T1544P,
348 14 P348A,
270 11 Q270K,
360 6
1552 11 Q1552L, Q1552R,
355 8 F355I, F355C,
1549 6
1556 14
356 4 D356N,
1543 13 V1543L, V1543A,
1542 15
361 6
904 14 W904X,
343 15
365 12
354 7
1546 9 M1546T,
1545 12
267 13
1550 9
262 13 S262G,
357 0
272 12
274 11 G274C,
362 10
261 14
273 8
1553 15 S1553R,
269 7
345 15
916 14
275 13 N275K,
264 15
912 13 Q912R,
347 12
1548 9 E1548K, G1548K,
351 11 G351D, G351S, G351V, G351C,
265 9 A265V,
358 6
1551 12 D1551N, D1551Y,
263 15 V263I,
346 14 E346K, E346G, E346D, E346X,
359 5 A359T, p.A359PfsX12,
1547 9 V1547L,
352 10 Y352C,
268 10 G268S,
353 11 T353I,
907 15