SCN5A Variant T512I Detail

We estimate the penetrance of LQTS for SCN5A T512I around 4% and the Brugada syndrome penetrance around 26%. SCN5A T512I was found in a total of 3 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. T512I is present in 1 alleles in gnomAD. T512I has been functionally characterized in 3 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 (2 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 T512I around 4% (0/13) and the Brugada syndrome penetrance around 26% (3/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.56 0.022 -0.83 0.54 32 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
12569159 2003 2 0 0 1 AV Block
27554632 2017 2 0 1 1 CM
LITERATURE, COHORT, AND GNOMAD: - 3 2 0 1 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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)
12569159 2003 HEK 100 -8.7 -7.5
12569154 2003
27554632 2017

T512I 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
497 15 S497C,
498 14
499 14
500 13 E500K,
501 13 D501G,
502 12
503 11 P503S,
504 11 R504T,
505 10 A505E,
506 9 M506K,
507 8 p.N507_L515dup,
508 8
509 7
510 5
511 4
512 0 T512I,
513 4 R513P, c.1537delC, R513H, R513C,
514 5 G514C,
515 7
516 8
517 8 R517S,
518 9
519 10 S519F,
520 11 M520R, M520V,
521 11 K521E, c.1562delA,
522 12 P522S,
523 13 R523S, R523C, R523H,
524 13 S524Y, c.1570_1571insG,
525 14 S525G,
526 14 R526C, R526H,
527 15 G527R,