SCN5A Variant c.1705dupC Detail

We estimate the penetrance of LQTS for SCN5A c.1705dupC around 6% and the Brugada syndrome penetrance around 16%. SCN5A c.1705dupC was found in a total of 4 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. c.1705dupC is not present in gnomAD. c.1705dupC has been functionally characterized in 1 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 (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 c.1705dupC around 6% (0/14) and the Brugada syndrome penetrance around 16% (2/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 8 10
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
26173111 2015 4 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 4 3 0 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)
26173111 2015

c.1705dupC 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
554 15 S554N, S554I,
555 14 E555K,
556 14
557 13 H557Y, H557Q, H557L,
558 13 H558R,
559 12 T559I, T559R,
560 11
561 11
562 10
563 9 V563G,
564 8
565 8
566 7
567 5 L567Q,
568 4 R568H, R568C,
569 0 c.1705dupC, R569Q, R569W,
570 4 T570N,
571 5 S571I,
572 7 A572S, A572D, A572F, A572V,
573 8 Q573X, Q573E, Q573R,
574 8 G574E, c.1721delG,
575 9
576 10
577 11 S577N,
578 11 P578T, P578R,
579 12 G579R,
580 13
581 13 S581L,
582 14
583 14 P583L,
584 15 G584R,