SCN5A Variant c.5157delC Detail

We estimate the penetrance of LQTS for SCN5A c.5157delC around 4% and the Brugada syndrome penetrance around 55%. SCN5A c.5157delC was found in a total of 1 carriers in 3 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. c.5157delC is not present in gnomAD. c.5157delC has been functionally characterized in 3 papers. This residue is located in a 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 (5 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.5157delC around 4% (0/11) and the Brugada syndrome penetrance around 55% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 76 2
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
17697823 2007 1 0 1 0
28341781 2017 1 0 1 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
20129283 2010
17697823 2007
28341781 2017

c.5157delC has 65 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
1746 9 A1746V, A1746T,
1724 14
1741 11 D1741Y, D1741N, D1741E,
1715 9
1687 10
1745 7
1756 15 I1756V,
1675 10
1743 6 G1743E, G1743R,
1723 11 T1723N,
1754 14
1707 12
1725 14 P1725L,
1681 13 Y1681F, c.5040_5042delTTAinsC,
1694 9
1704 14 L1704H,
1410 13
1706 15 Q1706H,
1747 8 V1747M,
1716 7 p.L1716SfsX71,
1695 13 Q1695X,
1714 10 D1714G,
1688 9
1684 12 W1684R,
1671 14
1676 13 M1676I, M1676T,
1692 14
1744 5 S1744I,
1721 4
1753 12 T1753A,
1672 14 S1672Y,
1742 10
1693 12
1712 12 G1712C, G1712S,
1680 10 A1680T, A1680P,
1703 12
1719 4
1731 14
1728 15 C1728W, C1728Y, C1728R,
1690 15 c.5068_5070delGA, D1690N,
1678 10 N1678S,
1755 14
1674 13 F1674V,
1399 11
1713 12
1748 6 G1748D, p.G1748del,
1683 9
1400 14 V1400I,
1718 6 S1718R,
1689 14 D1689N,
1700 14
1717 5 L1717P,
1751 9
1677 13
1682 7
1750 11 L1750F,
1752 8
1722 8 N1722D,
1686 10
1749 9 I1749N,
1740 12 G1740R,
1720 0 c.5157delC,
1679 7
1685 9
1414 14 Q1414H,