SCN5A Variant H472L Detail

We estimate the penetrance of LQTS for SCN5A H472L around 2% and the Brugada syndrome penetrance around 9%. SCN5A H472L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. H472L is not present in gnomAD. H472L 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 H472L around 2% (0/10) and the Brugada syndrome penetrance around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.111 10 1
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 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.

H472L 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
457 15
458 14 R458C, p.R458VfsX12, R458H,
459 14 S459G,
460 13
461 13 L461V,
462 12 E462K, E462A,
463 11 M463T, M463R,
464 11
465 10 p.P465LfsX5,
466 9 L466F,
467 8
468 8 P468L,
469 7 V469I,
470 5 N470K,
471 4
472 0
473 4 E473X,
474 5 R474K, R474G,
475 7 R475K, R475S,
476 8
477 8 c.1428_1431delCAAG,
478 9
479 10
480 11 K480N,
481 11 R481W, R481Q,
482 12 M482I,
483 13
484 13
485 14
486 14 T486S, T486A,
487 15