KCNH2 Variant I663C Detail

We estimate the penetrance of LQTS for KCNH2 I663C is 21%. We are unaware of any observations of this variant in individuals. I663C is not present in gnomAD. I663C has been functionally characterized in 1 papers. 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 I663C around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 22
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail 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. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
18955593 Xeno 22.6 None None 2.089588378

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
18955593 Xeno None None None

I663C has 48 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
663 0
662 5
664 5 Q664X,
660 5 S660L,
661 6 A661V,
666 6
667 6 Y667X,
659 6
654 7
665 8 R665Q,
550 8
658 9
668 9 S668L,
653 9
546 9
650 9 L650X,
657 10 G657V, G657S,
547 10 A547T,
658 10
657 10 G657V, G657S,
655 11
549 11 V549M,
671 11 A671Del, A671G,
670 11
656 11 F656L, F656L, F656L,
651 11 M651K,
669 12 G669R, G669C, G669X,
553 12 L553V,
554 12
548 12
655 13
661 13 A661V,
649 13
656 13 F656L, F656L, F656L,
659 14
553 14 L553V,
672 14 R672C, R672H,
660 14 S660L,
551 14 F551L, F551L, F551L,
675 14
678 14
648 14 G648A,
652 14 Y652X,
647 14
552 15 L552S,
654 15
674 15 H674fsX, H674Y,
662 15