SCN5A Variant P648L Detail

We estimate the penetrance of LQTS for SCN5A P648L around 10% and the Brugada syndrome penetrance around 10%. SCN5A P648L was found in a total of 17 carriers in 7 papers and/or in gnomAD: 1 had Brugada syndrome, 2 had LQTS. P648L is present in 14 alleles in gnomAD. P648L has been functionally characterized in 7 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 P648L around 10% (2/27) and the Brugada syndrome penetrance around 10% (2/27).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
0.47 0.011 -0.49 0.485 18 6
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
24613995 2014 1 0 0 1 irritable bowel syndrome
15840476 2005 1 1 0 0
19412328 2008 1 0 0 1 DCM
23631430 2013 1 1 0 0
26941339 2016 1 0 1 0
25904541 2015 1 1 0 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 17 14 2 1 -
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.

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)
15840476 2005
19412328 2008
23631430 2013
26941339 2016
25904541 2015
20129283 2010
24613995 2014 HEK 99 2 -0.5 45

P648L 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
633 15
634 14 S634L, S634W,
635 14
636 13 E636K,
637 13 P637L,
638 12 G638D,
639 11 G639R, G639A,
640 11 P640L, P640A, P640S,
641 10
642 9
643 8
644 8
645 7
646 5 p.Q646RfsX5, c.1936delC,
647 4 A647S, A647D, A647V,
648 0 P648L,
649 4 C649R, C649Y,
650 5
651 7 D651H, c.1950_1953delAGAT,
652 8 G652S, G652D,
653 8
654 9 E654X , E654K, E654D, E654Q,
655 10 E655K,
656 11 P656L,
657 11
658 12 A658V,
659 13 R659W, R659Q,
660 13
661 14 R661Q, R661W,
662 14 A662S, c.1983_1993dupGGCCCTCAGCG,
663 15