SCN5A Variant R1623X Detail

We estimate the penetrance of LQTS for SCN5A R1623X around 10% and the Brugada syndrome penetrance around 38%. SCN5A R1623X was found in a total of 11 carriers in 10 papers and/or in gnomAD: 5 had Brugada syndrome, 0 had LQTS. R1623X is not present in gnomAD. R1623X has been functionally characterized in 13 papers. This residue is located in a Mild_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 (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A R1623X around 10% (1/21) and the Brugada syndrome penetrance around 38% (7/21).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 29 39
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
28069705 2017 1 0 0 1 ARVD
16325048 2005 1 0 1 0
14523039 2003 4 0 0 1 SSS
15840483 2005 5 0 2 0
22885917 2012 1 0 1 0
28341781 2017 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
29574140 2018 1 0 1 0
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 11 6 0 5 -
VARIANT FEATURES ALONE: - 15 12 1 2 - -
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)
20539757 2010
15840483 2005
22885917 2012
28341781 2017
20129283 2010
20129283 2010
28069705 2017 0
28552050 2017 0
16325048 2005 HEK 0
20384651 2010 0
14523039 2003 HEK-tSA201 0
29574140 2018
30059973 2018