KCNH2 Variant N479I Detail

We estimate the penetrance of LQTS for KCNH2 N479I is 39%. We are unaware of any observations of this variant in individuals. N479I is not present in gnomAD. N479I 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N479I around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.34 0.992 -4 0.913 38
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: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 7 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.

N479I 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. 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
479 0
478 4 A478D,
480 5 E480V,
477 5
827 6
481 7
826 9 T826A, T826I,
476 9 V476I,
482 10 V482A,
765 10
703 11
483 11 V483I,
475 11 Y475C, Y475Del,
6 11 G6R,
764 11
828 12
4 12
20 12 R20L, R20G,
706 12 S706C, S706F,
9 12 A9T, A9V,
825 12
784 12 R784Q, R784W, R784G,
785 13 G785D, G785S, G785fsX,
492 13 H492Y,
829 13 D829E, D829E, D829A,
488 13 R488C, R488H,
16 13 D16A,
763 13
7 13
707 13
762 13
8 13
13 13 T13N,
786 14
699 14 E699D, E699D,
10 14
824 14
702 14
17 14
484 14
766 14
704 15 A704V, A704T,