SCN5A Variant G514R Detail

We estimate the penetrance of LQTS for SCN5A G514R around 3% and the Brugada syndrome penetrance around 37%. SCN5A G514R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. G514R is not present in gnomAD. G514R has been functionally characterized in 0 papers. This residue is located in a 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 (3 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 G514R around 3% (0/10) and the Brugada syndrome penetrance around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.465 56 0
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 12 0 3 - -
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.

G514R 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
499 15
500 14 E500K,
501 14 D501G,
502 13
503 13 P503S,
504 12 R504T,
505 11 A505E,
506 11 M506K,
507 10 p.N507_L515dup,
508 9
509 8
510 8
511 7
512 5 T512I,
513 4 c.1537delC, R513H, R513C, R513P,
514 0 G514C,
515 4
516 5
517 7 R517S,
518 8
519 8 S519F,
520 9 M520V, M520R,
521 10 c.1562delA, K521E,
522 11 P522S,
523 11 R523H, R523S, R523C,
524 12 S524Y, c.1570_1571insG,
525 13 S525G,
526 13 R526H, R526C,
527 14 G527R,
528 14 S528R,
529 15