SCN5A Variant L587R Detail

We estimate the penetrance of LQTS for SCN5A L587R around 3% and the Brugada syndrome penetrance around 8%. SCN5A L587R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L587R is not present in gnomAD. L587R 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 L587R around 3% (0/10) and the Brugada syndrome penetrance around 8% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.562 3 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.

L587R 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
572 15 A572S, A572D, A572F, A572V,
573 14 Q573X, Q573E, Q573R,
574 14 G574E, c.1721delG,
575 13
576 13
577 12 S577N,
578 11 P578T, P578R,
579 11 G579R,
580 10
581 9 S581L,
582 8
583 8 P583L,
584 7 G584R,
585 5
586 4 p.586_587delAL, A586G, A586T,
587 0
588 4 H588R, H588N,
589 5
590 7 K590Q,
591 8
592 8 N592K, N592S,
593 9
594 10
595 11
596 11 D596G,
597 12 C597Y, C597G,
598 13
599 13 G599R,
600 14
601 14 V601A,
602 15