SCN5A Variant L509H Detail

We estimate the penetrance of LQTS for SCN5A L509H around 8% and the Brugada syndrome penetrance around 16%. SCN5A L509H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L509H is not present in gnomAD. L509H 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 L509H around 8% (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 0.561 18 7
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.

L509H 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
494 15
495 14
496 14 K496N, K496M,
497 13 S497C,
498 13
499 12
500 11 E500K,
501 11 D501G,
502 10
503 9 P503S,
504 8 R504T,
505 8 A505E,
506 7 M506K,
507 5 p.N507_L515dup,
508 4
509 0
510 4
511 5
512 7 T512I,
513 8 R513C, R513H, R513P, c.1537delC,
514 8 G514C,
515 9
516 10
517 11 R517S,
518 11
519 12 S519F,
520 13 M520V, M520R,
521 13 K521E, c.1562delA,
522 14 P522S,
523 14 R523H, R523C, R523S,
524 15 c.1570_1571insG, S524Y,