SCN5A Variant R526H Detail

We estimate the penetrance of LQTS for SCN5A R526H around 1% and the Brugada syndrome penetrance around 25%. SCN5A R526H was found in a total of 20 carriers in 6 papers and/or in gnomAD: 6 had Brugada syndrome, 0 had LQTS. R526H is present in 14 alleles in gnomAD. R526H has been functionally characterized in 7 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 R526H around 1% (0/30) and the Brugada syndrome penetrance around 25% (7/30).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.94 0 2.91 0.476 14 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
24795344 2014 2 0 2 0
19412328 2008 1 0 0 1 DCM
23321620 2013 1 0 1 0
27554632 2017 4 0 1 3 CM
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 20 14 0 6 -
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.

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)
27554632 2017
24795344 2014 HEK 75
19412328 2008
23321620 2013
24573164 2014 HEK 88 -1.81
20129283 2010
20129283 2010

R526H 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
511 15
512 14 T512I,
513 14 R513C, R513P, R513H, c.1537delC,
514 13 G514C,
515 13
516 12
517 11 R517S,
518 11
519 10 S519F,
520 9 M520V, M520R,
521 8 K521E, c.1562delA,
522 8 P522S,
523 7 R523H, R523S, R523C,
524 5 c.1570_1571insG, S524Y,
525 4 S525G,
526 0 R526C, R526H,
527 4 G527R,
528 5 S528R,
529 7
530 8 F530S, F530V,
531 8 T531A, T531I,
532 9 F532L, F532C,
533 10 R533C, R533S, R533H,
534 11
535 11 R535X, R535G, R535Q,
536 12 D536H,
537 13
538 13 G538D,
539 14
540 14
541 15