SCN5A Variant L643R Detail

We estimate the penetrance of LQTS for SCN5A L643R around 13% and the Brugada syndrome penetrance around 18%. SCN5A L643R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L643R is not present in gnomAD. L643R 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 L643R around 13% (0/10) and the Brugada syndrome penetrance around 18% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.51 21 15
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.

L643R 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
628 15 P628R,
629 14 D629Y,
630 14 T630M,
631 13 c.1890+5G>A, c.1890G>A, p.T631VfsX101,
632 13 T632M,
633 12
634 11 S634W, S634L,
635 11
636 10 E636K,
637 9 P637L,
638 8 G638D,
639 8 G639A, G639R,
640 7 P640S, P640L, P640A,
641 5
642 4
643 0
644 4
645 5
646 7 c.1936delC, p.Q646RfsX5,
647 8 A647S, A647D, A647V,
648 8 P648L,
649 9 C649Y, C649R,
650 10
651 11 D651H, c.1950_1953delAGAT,
652 11 G652D, G652S,
653 12
654 13 E654K, E654X , E654D, E654Q,
655 13 E655K,
656 14 P656L,
657 14
658 15 A658V,