SCN5A Variant R513H Detail

We estimate the penetrance of LQTS for SCN5A R513H around 1% and the Brugada syndrome penetrance around 21%. SCN5A R513H was found in a total of 1 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R513H is present in 1 alleles in gnomAD. R513H has been functionally characterized in 2 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 R513H around 1% (0/11) and the Brugada syndrome penetrance around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
0.64 0 2 0.453 29 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
24529773 2014 1 0 0 1 SUNDS
27554632 2017 1 0 0 1 CM
LITERATURE, COHORT, AND GNOMAD: - 1 1 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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
24529773 2014
27554632 2017

R513H 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
498 15
499 14
500 14 E500K,
501 13 D501G,
502 13
503 12 P503S,
504 11 R504T,
505 11 A505E,
506 10 M506K,
507 9 p.N507_L515dup,
508 8
509 8
510 7
511 5
512 4 T512I,
513 0 c.1537delC, R513H, R513C, R513P,
514 4 G514C,
515 5
516 7
517 8 R517S,
518 8
519 9 S519F,
520 10 M520V, M520R,
521 11 c.1562delA, K521E,
522 11 P522S,
523 12 R523C, R523H, R523S,
524 13 S524Y, c.1570_1571insG,
525 13 S525G,
526 14 R526H, R526C,
527 14 G527R,
528 15 S528R,