SCN5A Variant G1740R Detail

We estimate the penetrance of LQTS for SCN5A G1740R around 6% and the Brugada syndrome penetrance around 50%. SCN5A G1740R was found in a total of 2 carriers in 4 papers and/or in gnomAD: 2 had Brugada syndrome, 0 had LQTS. G1740R is not present in gnomAD. G1740R has been functionally characterized in 4 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 (3 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 G1740R around 6% (0/12) and the Brugada syndrome penetrance around 50% (5/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.4 1 -0.52 0.982 48 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
15057319 2004 1 0 1 0
11901046 2002 1 0 1 0
19251209 2009 1 0 1 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 0 2 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
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)
11901046 2002
19251209 2009
20129283 2010
15057319 2004 HEK-tSA202 0

G1740R has 42 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
1741 4 D1741Y, D1741N, D1741E,
1745 14
1675 14
1743 7 G1743R, G1743E,
1681 6 c.5040_5042delTTAinsC, Y1681F,
1694 13
1737 10 G1737D,
1226 14
1747 14 V1747M,
1695 11 Q1695X,
1688 15
1684 13 W1684R,
1676 14 M1676I, M1676T,
1744 11 S1744I,
1721 14
1742 5
1733 9
1693 14
1738 7 S1738T, S1738F,
1680 7 A1680P, A1680T,
1719 13
1731 7
1728 14 C1728R, C1728Y, C1728W,
1690 15 D1690N, c.5068_5070delGA,
1678 11 N1678S,
1227 12
1300 14
1735 11
1730 11 P1730L, P1730H, P1730A,
1683 8
1739 5 R1739Q, R1739W,
1734 9
1677 12
1682 7
1722 13 N1722D,
1729 13 D1729N,
1740 0 G1740R,
1720 12 c.5157delC,
1732 5
1736 13
1679 11
1685 14