SCN5A Variant F358I Detail

We estimate the penetrance of LQTS for SCN5A F358I around 8% and the Brugada syndrome penetrance around 27%. SCN5A F358I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F358I is not present in gnomAD. F358I 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 F358I around 8% (0/10) and the Brugada syndrome penetrance around 27% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.954 34 6
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.

F358I has 53 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 10
271 13 L271V,
266 7 L266H,
363 10
1544 11 T1544P,
270 10 Q270K,
360 9
1627 13
396 15 V396A, V396L,
1552 14 Q1552R, Q1552L,
355 9 F355I, F355C,
1549 10
356 9 D356N,
1543 10 V1543A, V1543L,
1542 10
361 5
260 13
366 13
365 10
258 11 V258A,
354 11
1546 5 M1546T,
1545 10
267 10
1550 13
262 7 S262G,
357 6
272 13
274 14 G274C,
362 6
261 9
273 11
1539 14 C1539Y, C1539F,
392 15
269 6
916 14
264 11
259 12
1548 10 E1548K, G1548K,
265 6 A265V,
358 0
367 15 R367H, R367C, R367L,
263 10 V263I,
359 5 A359T, p.A359PfsX12,
1547 9 V1547L,
1541 14
1540 15
352 14 Y352C,
368 14
268 9 G268S,
257 14
353 14 T353I,
1623 14 R1623Q, R1623X, c.4867delC, R1623L,