SCN5A Variant L676S Detail

We estimate the penetrance of LQTS for SCN5A L676S around 9% and the Brugada syndrome penetrance around 25%. SCN5A L676S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L676S is not present in gnomAD. L676S 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 L676S around 9% (0/10) and the Brugada syndrome penetrance around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.801 31 9
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.

L676S 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
661 15 R661Q, R661W,
662 14 c.1983_1993dupGGCCCTCAGCG, A662S,
663 14
664 13 S664G,
665 13 A665T, A665S,
666 12
667 11
668 11 V668I,
669 10
670 9
671 8 S671C,
672 8 A672S, A672T,
673 7 L673V, L673P,
674 5
675 4 c.2024_2025delAG,
676 0
677 4 E677V,
678 5
679 7
680 8 R680H, R680C,
681 8 H681P,
682 9
683 10 C683S, C683G, C683R,
684 11
685 11
686 12 C686F,
687 13
688 13
689 14 R689C, R689H,
690 14
691 15 A691T, A691S,