SCN5A Variant I391V Detail

We estimate the penetrance of LQTS for SCN5A I391V around 10% and the Brugada syndrome penetrance around 22%. SCN5A I391V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I391V is not present in gnomAD. I391V has been functionally characterized in 0 papers. This residue is located in a Mild_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 (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 I391V around 10% (0/10) and the Brugada syndrome penetrance around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.406 30 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 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.

I391V has 50 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
271 11 L271V,
1702 11
387 10
396 10 V396L, V396A,
385 12 A385T,
1624 12 V1624I,
391 0
330 15 S330F,
388 7 I388S,
1698 13 A1698T,
365 15
1704 15 L1704H,
1706 14 Q1706H,
1668 14 M1668T,
386 10 G386E, G386R,
378 11
1699 15
331 15
402 15 F402L,
1665 13
267 11
1625 15
399 11
272 12
397 11 I397V, I397F, I397T,
1628 15
1701 12 M1701I,
392 6
1697 15
389 7 Y389X, Y389H,
1620 12 T1620K, T1620M,
395 6
393 7
390 5
394 5
264 11
382 11
374 14 W374G,
1705 10
263 15 V263I,
1661 14 G1661R, G1661E,
381 12 c.1140+1G>A, c.1141-3C>A,
368 13
268 13 G268S,
377 15
398 11
400 14 G400E, G400A, G400R,
1621 12
1664 14
1658 15