SCN5A Variant S476C Detail

We estimate the penetrance of LQTS for SCN5A S476C around 2% and the Brugada syndrome penetrance around 23%. SCN5A S476C was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S476C is not present in gnomAD. S476C 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 (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 S476C around 2% (0/10) and the Brugada syndrome penetrance around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.361 32 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 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.

S476C 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
461 15 L461V,
462 14 E462K, E462A,
463 14 M463T, M463R,
464 13
465 13 p.P465LfsX5,
466 12 L466F,
467 11
468 11 P468L,
469 10 V469I,
470 9 N470K,
471 8
472 8
473 7 E473X,
474 5 R474G, R474K,
475 4 R475K, R475S,
476 0
477 4 c.1428_1431delCAAG,
478 5
479 7
480 8 K480N,
481 8 R481W, R481Q,
482 9 M482I,
483 10
484 11
485 11
486 12 T486S, T486A,
487 13
488 13
489 14
490 14 G490E, G490A,
491 15 E491G,