SCN5A Variant C649S Detail

We estimate the penetrance of LQTS for SCN5A C649S around 4% and the Brugada syndrome penetrance around 11%. SCN5A C649S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. C649S is not present in gnomAD. C649S has been functionally characterized in 0 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 (1 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 C649S around 4% (0/10) and the Brugada syndrome penetrance around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.406 10 3
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 14 0 1 - -
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.

C649S 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
634 15 S634W, S634L,
635 14
636 14 E636K,
637 13 P637L,
638 13 G638D,
639 12 G639A, G639R,
640 11 P640S, P640L, P640A,
641 11
642 10
643 9
644 8
645 8
646 7 c.1936delC, p.Q646RfsX5,
647 5 A647S, A647D, A647V,
648 4 P648L,
649 0 C649Y, C649R,
650 4
651 5 D651H, c.1950_1953delAGAT,
652 7 G652D, G652S,
653 8
654 8 E654K, E654X , E654D, E654Q,
655 9 E655K,
656 10 P656L,
657 11
658 11 A658V,
659 12 R659Q, R659W,
660 13
661 13 R661Q, R661W,
662 14 c.1983_1993dupGGCCCTCAGCG, A662S,
663 14
664 15 S664G,