SCN5A Variant L624Q Detail

We estimate the penetrance of LQTS for SCN5A L624Q around 3% and the Brugada syndrome penetrance around 12%. SCN5A L624Q was found in a total of 2 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L624Q is present in 2 alleles in gnomAD. L624Q 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 (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 L624Q around 3% (0/12) and the Brugada syndrome penetrance around 12% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.16 0.6 0.28 0.586 12 3
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: - 2 2 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.

L624Q 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
609 15
610 14 E610K,
611 14
612 13
613 13
614 12 P614S,
615 11 G615E,
616 11 S616N,
617 10
618 9 L618F,
619 8 L619F,
620 8 R620C, R620H,
621 7
622 5
623 4 M623T,
624 0 L624Q,
625 4 c.1872dupA, E625Q, E625D,
626 5
627 7 P627L,
628 8 P628R,
629 8 D629Y,
630 9 T630M,
631 10 c.1890G>A, c.1890+5G>A, p.T631VfsX101,
632 11 T632M,
633 11
634 12 S634L, S634W,
635 13
636 13 E636K,
637 14 P637L,
638 14 G638D,
639 15 G639R, G639A,