SCN5A Variant L461V Detail

We estimate the penetrance of LQTS for SCN5A L461V around 0% and the Brugada syndrome penetrance around 0%. SCN5A L461V was found in a total of 333 carriers in 3 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L461V is present in 329 alleles in gnomAD. L461V has been functionally characterized in 3 papers. This residue is located in a Non_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 (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 L461V around 0% (0/343) and the Brugada syndrome penetrance around 0% (0/343).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.55 0.08 -0.94 None 1 23
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
16712702 2006 1 0 0 1 Sudden adult death syndrome
22818067 2012 6 0 0 4 AF
20129283 2010 2 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 333 333 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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
16712702 2006
22818067 2012
20129283 2010

L461V 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
446 15 E446K,
447 14 c.1338+2T>A, c.1339-24G>A, A447G, A447S,
448 14
449 13 T449A, Y449C,
450 13
451 12
452 11 G452D,
453 11 V453M,
454 10
455 9
456 8 V456M,
457 8
458 7 R458C, p.R458VfsX12, R458H,
459 5 S459G,
460 4
461 0 L461V,
462 4 E462A, E462K,
463 5 M463R, M463T,
464 7
465 8 p.P465LfsX5,
466 8 L466F,
467 9
468 10 P468L,
469 11 V469I,
470 11 N470K,
471 12
472 13
473 13 E473X,
474 14 R474K, R474G,
475 14 R475K, R475S,
476 15