SCN5A Variant L511I Detail

We estimate the penetrance of LQTS for SCN5A L511I around 3% and the Brugada syndrome penetrance around 22%. SCN5A L511I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L511I is not present in gnomAD. L511I 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 L511I around 3% (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 0.399 29 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 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.

L511I has 31 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
496 15 K496M, K496N,
497 14 S497C,
498 14
499 13
500 13 E500K,
501 12 D501G,
502 11
503 11 P503S,
504 10 R504T,
505 9 A505E,
506 8 M506K,
507 8 p.N507_L515dup,
508 7
509 5
510 4
511 0
512 4 T512I,
513 5 R513P, R513C, R513H, c.1537delC,
514 7 G514C,
515 8
516 8
517 9 R517S,
518 10
519 11 S519F,
520 11 M520R, M520V,
521 12 K521E, c.1562delA,
522 13 P522S,
523 13 R523H, R523S, R523C,
524 14 c.1570_1571insG, S524Y,
525 14 S525G,
526 15 R526H, R526C,