SCN5A Variant I388T Detail

We estimate the penetrance of LQTS for SCN5A I388T around 4% and the Brugada syndrome penetrance around 16%. SCN5A I388T was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I388T is not present in gnomAD. I388T 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 (1 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 I388T around 4% (0/10) and the Brugada syndrome penetrance around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.515 17 2
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 14 0 1 - -
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.

I388T has 49 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 12
333 13 c.998+5G>A, c.998+1G>A,
271 11 L271V,
1702 10
276 15 L276Q, L276P,
387 5
396 15 V396L, V396A,
385 7 A385T,
1624 14 V1624I,
391 7
330 8 S330F,
388 0 I388S,
1698 10 A1698T,
334 15 c.999-424_1338+81del,
332 9 A332T,
327 13
384 11 S384T,
329 9
1692 13
386 5 G386E, G386R,
378 11
1699 12
331 9
267 14
379 14
1703 15
272 11
1701 12 M1701I,
392 10
1697 13
389 4 Y389X, Y389H,
1620 11 T1620K, T1620M,
395 12
393 10
390 6
394 11
275 13 N275K,
383 13
382 8
1619 15 P1619Q, c.4856delC, P1619L,
1696 15
1705 12
1700 14
381 10 c.1140+1G>A, c.1141-3C>A,
1691 12
380 15
268 14 G268S,
1618 14
1621 12