KCNH2 Variant I684N Detail

We estimate the penetrance of LQTS for KCNH2 I684N is 23%. We are unaware of any observations of this variant in individuals. I684N is not present in gnomAD. I684N 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I684N around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.806 0.614 -4 0.929 21
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 8 2 -
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.

I684N has 51 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
684 0
689 5
683 5
685 6 R685C, R685H, R685P,
680 6
694 6 R694H, R694C,
687 7
681 7 R681W,
688 7
682 7 E682X,
686 8
697 8 L697X,
690 8
698 9 E698K, E698X,
693 9 L693X,
728 10
677 10 M677T,
678 10
731 10 H731R,
691 10
716 11 V716G,
713 11 M713V,
679 11 R679Q, R679W,
711 11 I711V,
732 11
695 12
692 12
709 12
720 12
717 12 L717P,
701 12
708 13
696 13 R696H, R696C,
727 13
676 13 Q676X, Q676fsX,
724 13 L724X,
707 13
729 14
699 14 E699D, E699D,
544 14 E544fsX, E544A,
734 14 R734H, R734C,
715 14 A715A, A715T, A715sp, A715V,
710 14
712 14 D712N,
702 14
700 15
725 15 Q725R, Q725fsX,
5 15
675 15
545 15
719 15