SCN5A Variant P578R Detail

We estimate the penetrance of LQTS for SCN5A P578R around 4% and the Brugada syndrome penetrance around 6%. SCN5A P578R was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. P578R is present in 1 alleles in gnomAD. P578R 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 P578R around 4% (0/11) and the Brugada syndrome penetrance around 6% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.02 1 -0.05 0.278 2 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: - 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.

P578R 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
563 15 V563G,
564 14
565 14
566 13
567 13 L567Q,
568 12 R568H, R568C,
569 11 c.1705dupC, R569W, R569Q,
570 11 T570N,
571 10 S571I,
572 9 A572D, A572V, A572F, A572S,
573 8 Q573E, Q573R, Q573X,
574 8 c.1721delG, G574E,
575 7
576 5
577 4 S577N,
578 0 P578T, P578R,
579 4 G579R,
580 5
581 7 S581L,
582 8
583 8 P583L,
584 9 G584R,
585 10
586 11 A586T, p.586_587delAL, A586G,
587 11
588 12 H588R, H588N,
589 13
590 13 K590Q,
591 14
592 14 N592K, N592S,
593 15