SCN5A Variant H508Q Detail

We estimate the penetrance of LQTS for SCN5A H508Q around 9% and the Brugada syndrome penetrance around 12%. SCN5A H508Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. H508Q is not present in gnomAD. H508Q 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 H508Q around 9% (0/10) and the Brugada syndrome penetrance around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.478 11 10
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.

H508Q 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
493 15 R493K,
494 14
495 14
496 13 K496N, K496M,
497 13 S497C,
498 12
499 11
500 11 E500K,
501 10 D501G,
502 9
503 8 P503S,
504 8 R504T,
505 7 A505E,
506 5 M506K,
507 4 p.N507_L515dup,
508 0
509 4
510 5
511 7
512 8 T512I,
513 8 R513H, R513P, R513C, c.1537delC,
514 9 G514C,
515 10
516 11
517 11 R517S,
518 12
519 13 S519F,
520 13 M520R, M520V,
521 14 K521E, c.1562delA,
522 14 P522S,
523 15 R523S, R523C, R523H,