KCNH2 Variant I662C Detail

We estimate the penetrance of LQTS for KCNH2 I662C is 15%. We are unaware of any observations of this variant in individuals. I662C is not present in gnomAD. I662C 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I662C around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 13
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 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.

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 -14.2 None None 3.231638418

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

I662C has 53 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
662 0
661 4 A661V,
665 5 R665Q,
663 5
659 5
666 6
660 6 S660L,
658 6
546 7
550 7
549 7 V549M,
664 7 Q664X,
547 8 A547T,
657 8 G657V, G657S,
553 9 L553V,
667 9 Y667X,
548 10
668 10 S668L,
674 10 H674Y, H674fsX,
656 10 F656L, F656L, F656L,
655 11
654 11
543 11 S543fsX,
671 11 A671Del, A671G,
675 11
554 12
552 12 L552S,
678 12
650 12 L650X,
653 12
664 12 Q664X,
654 12
551 12 F551L, F551L, F551L,
545 12
657 13 G657V, G657S,
658 13
670 13
671 13 A671Del, A671G,
669 13 G669C, G669X, G669R,
670 14
544 14 E544fsX, E544A,
653 14
660 14 S660L,
555 15
649 15
673 15
556 15
663 15
651 15 M651K,
539 15
655 15
672 15 R672H, R672C,
677 15 M677T,