SCN5A Variant H626Y Detail

We estimate the penetrance of LQTS for SCN5A H626Y around 8% and the Brugada syndrome penetrance around 16%. SCN5A H626Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. H626Y is not present in gnomAD. H626Y 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 H626Y around 8% (0/10) and the Brugada syndrome penetrance around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.378 19 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 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.

H626Y 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
611 15
612 14
613 14
614 13 P614S,
615 13 G615E,
616 12 S616N,
617 11
618 11 L618F,
619 10 L619F,
620 9 R620H, R620C,
621 8
622 8
623 7 M623T,
624 5 L624Q,
625 4 E625Q, c.1872dupA, E625D,
626 0
627 4 P627L,
628 5 P628R,
629 7 D629Y,
630 8 T630M,
631 8 c.1890+5G>A, c.1890G>A, p.T631VfsX101,
632 9 T632M,
633 10
634 11 S634L, S634W,
635 11
636 12 E636K,
637 13 P637L,
638 13 G638D,
639 14 G639R, G639A,
640 14 P640L, P640A, P640S,
641 15