SCN5A Variant E625G Detail

We estimate the penetrance of LQTS for SCN5A E625G around 5% and the Brugada syndrome penetrance around 21%. SCN5A E625G was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E625G is not present in gnomAD. E625G 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 E625G around 5% (0/10) and the Brugada syndrome penetrance around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.49 27 3
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.

E625G 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
610 15 E610K,
611 14
612 14
613 13
614 13 P614S,
615 12 G615E,
616 11 S616N,
617 11
618 10 L618F,
619 9 L619F,
620 8 R620H, R620C,
621 8
622 7
623 5 M623T,
624 4 L624Q,
625 0 E625Q, E625D, c.1872dupA,
626 4
627 5 P627L,
628 7 P628R,
629 8 D629Y,
630 8 T630M,
631 9 c.1890G>A, c.1890+5G>A, p.T631VfsX101,
632 10 T632M,
633 11
634 11 S634W, S634L,
635 12
636 13 E636K,
637 13 P637L,
638 14 G638D,
639 14 G639R, G639A,
640 15 P640S, P640A, P640L,