KCNH2 Variant N12D Detail

We estimate the penetrance of LQTS for KCNH2 N12D is 10%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. N12D is present in 1 alleles in gnomAD. N12D has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N12D around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.769 0.081 0 0.683 12
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 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 LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 9 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.

N12D has 59 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. NOTE: some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. 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
12 0 N12D,
11 4 Q11H, Q11L, Q11H,
13 5 T13N,
14 5
10 6
15 6 L15V,
788 7 E788D, E788D, E788K,
795 7 V795I,
825 7
9 9 A9T, A9V,
823 9 R823W, R823fsX, R823Q, R823T,
790 9
16 9 D16A,
824 10
793 10 D793N,
124 10 M124R, M124T,
794 10 V794D, V794I,
798 10 I798fsX,
123 10
797 10 A797T,
786 10
17 11
766 11
789 11
796 11 V796L, V796Del, V796L,
33 11 N33T,
18 11 I18M,
42 11 I42N,
787 11
826 11 T826I, T826A,
765 12
8 12
31 12 I31S,
117 12
792 12
19 12 I19F,
115 12 V115M,
822 13 V822M, V822L, V822L,
32 13 A32T,
7 13
821 13 D821E, D821E,
799 13 L799sp,
43 13 Y43D, Y43C,
35 13 R35W,
767 14 D767X,
34 14 A34T,
785 14 G785D, G785S, G785fsX,
768 14
121 14 A121fsX,
122 14
828 14
791 15 R791W, R791Q,
764 15
116 15 K116Q,
118 15 E118D, E118X, E118K, E118D,
36 15 V36X,
800 15
125 15
126 15