SCN5A Variant T630K Detail

We estimate the penetrance of LQTS for SCN5A T630K around 16% and the Brugada syndrome penetrance around 19%. SCN5A T630K was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T630K is not present in gnomAD. T630K 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 T630K around 16% (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 0.623 23 19
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.

T630K 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
615 15 G615E,
616 14 S616N,
617 14
618 13 L618F,
619 13 L619F,
620 12 R620H, R620C,
621 11
622 11
623 10 M623T,
624 9 L624Q,
625 8 E625Q, c.1872dupA, E625D,
626 8
627 7 P627L,
628 5 P628R,
629 4 D629Y,
630 0 T630M,
631 4 c.1890+5G>A, c.1890G>A, p.T631VfsX101,
632 5 T632M,
633 7
634 8 S634L, S634W,
635 8
636 9 E636K,
637 10 P637L,
638 11 G638D,
639 11 G639R, G639A,
640 12 P640L, P640A, P640S,
641 13
642 13
643 14
644 14
645 15