SCN5A Variant N1065T Detail

We estimate the penetrance of LQTS for SCN5A N1065T around 4% and the Brugada syndrome penetrance around 6%. SCN5A N1065T was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. N1065T is not present in gnomAD. N1065T has been functionally characterized in 0 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 (0 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 N1065T around 4% (0/10) and the Brugada syndrome penetrance around 6% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.24 2 3
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

N1065T 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
1050 15 p.A1050DfsX9, A1050T, p.A1050CfsX9,
1051 14 V1051A,
1052 14 p.A1052CfsX7, A1052D,
1053 13 E1053K,
1054 13
1055 12 D1055G,
1056 11 T1056A,
1057 11
1058 10 c.3171_3172delTGinsA,
1059 9 Q1059X,
1060 8
1061 8 E1061D,
1062 7 D1062H,
1063 5 E1063G,
1064 4 p.E1064del,
1065 0
1066 4 S1066G,
1067 5 L1067R,
1068 7 G1068D, G1068A,
1069 8 T1069M,
1070 8
1071 9 E1071K, p.E1071GfsX76,
1072 10 p.E1072del,
1073 11
1074 11 S1074G, S1074R,
1075 12
1076 13
1077 13 c.3228+2delT,
1078 14
1079 14 S1079T, S1079Y, S1079F,
1080 15