SCN5A Variant R1913C Detail

We estimate the penetrance of LQTS for SCN5A R1913C around 3% and the Brugada syndrome penetrance around 18%. SCN5A R1913C was found in a total of 4 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. R1913C is present in 2 alleles in gnomAD. R1913C has been functionally characterized in 2 papers. This residue is located in a Non_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 R1913C around 3% (0/14) and the Brugada syndrome penetrance around 18% (2/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.34 1 -6.01 0.9 10 4
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
15996170 2005 1 0 0 0
28341781 2017 1 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)
28341781 2017
15996170 2005

R1913C 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
1898 15 R1898C, R1898H,
1899 14
1900 14
1901 13 E1901K, E1901Q,
1902 13 E1902A,
1903 12 V1903M,
1904 11 S1904L,
1905 11
1906 10 M1906T, M1906V,
1907 9
1908 8 I1908V,
1909 8 Q1909R,
1910 7 R1910K,
1911 5
1912 4
1913 0 R1913S, R1913H, R1913C,
1914 4 R1914G,
1915 5 H1915P, H1915Q, H1915N, H1915Y,
1916 7
1917 8
1918 8
1919 9 R1919H, R1919C,
1920 10 S1920C,
1921 11
1922 11 K1922N, K1922R,
1923 12 H1923Y, H1923D,
1924 13 A1924T,
1925 13 S1925F, p.S1925CfsX20,
1926 14
1927 14 L1927P,
1928 15 F1928V,