SCN5A Variant E674A Detail

We estimate the penetrance of LQTS for SCN5A E674A around 17% and the Brugada syndrome penetrance around 19%. SCN5A E674A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E674A is not present in gnomAD. E674A has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_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 E674A around 17% (0/10) and the Brugada syndrome penetrance around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.646 22 20
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 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.

E674A 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
659 15 R659Q, R659W,
660 14
661 14 R661Q, R661W,
662 13 c.1983_1993dupGGCCCTCAGCG, A662S,
663 13
664 12 S664G,
665 11 A665T, A665S,
666 11
667 10
668 9 V668I,
669 8
670 8
671 7 S671C,
672 5 A672S, A672T,
673 4 L673V, L673P,
674 0
675 4 c.2024_2025delAG,
676 5
677 7 E677V,
678 8
679 8
680 9 R680H, R680C,
681 10 H681P,
682 11
683 11 C683S, C683G, C683R,
684 12
685 13
686 13 C686F,
687 14
688 14
689 15 R689C, R689H,