SCN5A Variant G639R Detail

We estimate the penetrance of LQTS for SCN5A G639R around 34% and the Brugada syndrome penetrance around 6%. SCN5A G639R was found in a total of 3 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 2 had LQTS. G639R is present in 1 alleles in gnomAD. G639R has been functionally characterized in 2 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Mild_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 G639R around 34% (2/13) and the Brugada syndrome penetrance around 6% (0/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
1.72 0.001 1.27 0.49 5 24
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
16922724 2006 1 1 0 0
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 1 2 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.

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)
19716085 2009
16922724 2006

G639R 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
624 15 L624Q,
625 14 E625Q, E625D, c.1872dupA,
626 14
627 13 P627L,
628 13 P628R,
629 12 D629Y,
630 11 T630M,
631 11 p.T631VfsX101, c.1890G>A, c.1890+5G>A,
632 10 T632M,
633 9
634 8 S634L, S634W,
635 8
636 7 E636K,
637 5 P637L,
638 4 G638D,
639 0 G639A, G639R,
640 4 P640A, P640S, P640L,
641 5
642 7
643 8
644 8
645 9
646 10 c.1936delC, p.Q646RfsX5,
647 11 A647V, A647S, A647D,
648 11 P648L,
649 12 C649R, C649Y,
650 13
651 13 D651H, c.1950_1953delAGAT,
652 14 G652D, G652S,
653 14
654 15 E654K, E654Q, E654D, E654X ,