SCN5A Variant R475K Detail

We estimate the penetrance of LQTS for SCN5A R475K around 6% and the Brugada syndrome penetrance around 20%. SCN5A R475K was found in a total of 2 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. R475K is present in 1 alleles in gnomAD. R475K has been functionally characterized in 1 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 R475K around 6% (0/12) and the Brugada syndrome penetrance around 20% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.36 0.316 1.53 0.23 22 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
25650408 2015 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 1 0 1 -
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)
25650408 2015

R475K 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
460 15
461 14 L461V,
462 14 E462K, E462A,
463 13 M463R, M463T,
464 13
465 12 p.P465LfsX5,
466 11 L466F,
467 11
468 10 P468L,
469 9 V469I,
470 8 N470K,
471 8
472 7
473 5 E473X,
474 4 R474K, R474G,
475 0 R475K, R475S,
476 4
477 5 c.1428_1431delCAAG,
478 7
479 8
480 8 K480N,
481 9 R481W, R481Q,
482 10 M482I,
483 11
484 11
485 12
486 13 T486A, T486S,
487 13
488 14
489 14
490 15 G490A, G490E,