SCN5A Variant p.N507_L515dup Detail

We estimate the penetrance of LQTS for SCN5A p.N507_L515dup around 8% and the Brugada syndrome penetrance around 9%. SCN5A p.N507_L515dup was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. p.N507_L515dup is present in 1 alleles in gnomAD. p.N507_L515dup has been functionally characterized in 0 papers. This residue is located in a Non_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 (0 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 p.N507_L515dup around 8% (0/11) and the Brugada syndrome penetrance around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 4 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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

p.N507_L515dup 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
492 15
493 14 R493K,
494 14
495 13
496 13 K496N, K496M,
497 12 S497C,
498 11
499 11
500 10 E500K,
501 9 D501G,
502 8
503 8 P503S,
504 7 R504T,
505 5 A505E,
506 4 M506K,
507 0 p.N507_L515dup,
508 4
509 5
510 7
511 8
512 8 T512I,
513 9 R513C, R513P, c.1537delC, R513H,
514 10 G514C,
515 11
516 11
517 12 R517S,
518 13
519 13 S519F,
520 14 M520R, M520V,
521 14 K521E, c.1562delA,
522 15 P522S,