SCN5A Variant T719S Detail

We estimate the penetrance of LQTS for SCN5A T719S around 3% and the Brugada syndrome penetrance around 11%. SCN5A T719S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T719S is not present in gnomAD. T719S has been functionally characterized in 0 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 (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 T719S around 3% (0/10) and the Brugada syndrome penetrance around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.416 9 1
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.

T719S has 41 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
719 0
723 6 I723V,
818 15
710 10
766 11
758 14 G758E,
715 10 M715T, M715I,
728 15 V728I,
820 13
713 6
712 10
762 11
725 10
727 12
763 7 E763D, E763K,
767 9
717 7 P717L,
726 10
770 13
771 13 L771V,
720 4
785 13 D785N,
821 13
756 14
769 15
722 5
760 12 p.F760SfsX5,
714 6 V714D, V714A,
776 15 p.Y776del,
768 14
721 6
765 13
716 5
817 12 K817E,
759 11 c.2274delG, p.I759FfsX6, I759V,
761 14
711 12
724 9 T724I,
718 6 F718L,
764 11 M764R, M764K,
782 14 N782T,