SCN5A Variant E654X Detail

We estimate the penetrance of LQTS for SCN5A E654X around 5% and the Brugada syndrome penetrance around 17%. SCN5A E654X was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. E654X is not present in gnomAD. E654X has been functionally characterized in 1 papers. This residue is located in a Non_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 (0 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 E654X around 5% (0/11) and the Brugada syndrome penetrance around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 3 4
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
29381953 2017 1 0 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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)
29381953 2017

E654X 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
639 15 G639A, G639R,
640 14 P640S, P640L, P640A,
641 14
642 13
643 13
644 12
645 11
646 11 c.1936delC, p.Q646RfsX5,
647 10 A647S, A647D, A647V,
648 9 P648L,
649 8 C649Y, C649R,
650 8
651 7 D651H, c.1950_1953delAGAT,
652 5 G652D, G652S,
653 4
654 0 E654K, E654X , E654D, E654Q,
655 4 E655K,
656 5 P656L,
657 7
658 8 A658V,
659 8 R659Q, R659W,
660 9
661 10 R661Q, R661W,
662 11 c.1983_1993dupGGCCCTCAGCG, A662S,
663 11
664 12 S664G,
665 13 A665T, A665S,
666 13
667 14
668 14 V668I,
669 15