SCN5A Variant R517G Detail

We estimate the penetrance of LQTS for SCN5A R517G around 3% and the Brugada syndrome penetrance around 16%. SCN5A R517G was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R517G is not present in gnomAD. R517G 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 R517G around 3% (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 0.543 17 1
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.

R517G 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
502 15
503 14 P503S,
504 14 R504T,
505 13 A505E,
506 13 M506K,
507 12 p.N507_L515dup,
508 11
509 11
510 10
511 9
512 8 T512I,
513 8 R513P, c.1537delC, R513C, R513H,
514 7 G514C,
515 5
516 4
517 0 R517S,
518 4
519 5 S519F,
520 7 M520R, M520V,
521 8 K521E, c.1562delA,
522 8 P522S,
523 9 R523H, R523C, R523S,
524 10 c.1570_1571insG, S524Y,
525 11 S525G,
526 11 R526H, R526C,
527 12 G527R,
528 13 S528R,
529 13
530 14 F530V, F530S,
531 14 T531A, T531I,
532 15 F532L, F532C,