SCN5A Variant T580I Detail

We estimate the penetrance of LQTS for SCN5A T580I around 3% and the Brugada syndrome penetrance around 6%. SCN5A T580I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T580I is not present in gnomAD. T580I 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 T580I around 3% (0/10) and the Brugada syndrome penetrance around 6% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.269 2 2
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.

T580I 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
565 15
566 14
567 14 L567Q,
568 13 R568H, R568C,
569 13 R569Q, R569W, c.1705dupC,
570 12 T570N,
571 11 S571I,
572 11 A572D, A572F, A572V, A572S,
573 10 Q573R, Q573E, Q573X,
574 9 G574E, c.1721delG,
575 8
576 8
577 7 S577N,
578 5 P578T, P578R,
579 4 G579R,
580 0
581 4 S581L,
582 5
583 7 P583L,
584 8 G584R,
585 8
586 9 p.586_587delAL, A586G, A586T,
587 10
588 11 H588R, H588N,
589 11
590 12 K590Q,
591 13
592 13 N592S, N592K,
593 14
594 14
595 15