KCNH2 Variant I642C Detail

We estimate the penetrance of LQTS for KCNH2 I642C is 75%. We are unaware of any observations of this variant in individuals. I642C is not present in gnomAD. I642C has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I642C around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 79
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 3 7 -
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)
19892745 Xeno -15.7 None None None

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)
19892745 Xeno None None None

I642C has 69 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
642 0 I642Del, I642V,
641 4 S641F, S641P,
645 5 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
643 5
639 5 I639F, I639N,
619 6
616 6 Y616S,
644 6 V644F, V644I,
615 7 L615V, L615F,
646 7
640 7 F640L, F640V, F640L, F640L, F640Del,
638 7 K638Del, K638E, K638D, K638R,
612 8 V612L, V612A, V612L,
620 8 S620I, S620G,
618 9 T618S, T618S,
647 9
621 10 S621N, S621R, S621R, S621R,
623 10 T623I,
632 10 P632S, P632A,
558 10 A558V, A558P, A558E,
614 10 A614T, A614V,
561 10 A561V, A561P, A561T,
613 10 T613A, T613L, T613K, T613M,
636 10
627 10 F627X, F627L, F627fsX, F627L, F627L,
637 10 E637G, E637X, E637K,
648 10 G648A,
557 11
611 11 Y611D,
617 11 F617V, F617L, F617L, F617L,
649 11
625 11 V625E,
635 11 N635I,
622 11 L622F,
621 12 S621N, S621R, S621R, S621R,
622 12 L622F,
562 12 H562Q, H562Q, H562R, H562P,
617 12 F617V, F617L, F617L, F617L,
565 12
634 12 T634S, T634I, T634S, T634P, T634A,
626 12 G626A, G626S, G626V,
568 12 W568C, W568C,
564 12 L564L,
618 12 T618S, T618S,
554 12
624 13 S624R, S624R, S624R, S624N,
609 13 D609N, D609G,
631 13 S631F,
630 13 V630I, V630T, V630A,
629 13 N629K, N629S, N629K, N629I, N629D, N629T,
650 13 L650X,
624 13 S624R, S624R, S624R, S624N,
620 13 S620I, S620G,
633 13 N633D, N633I, N633S,
560 13 I560fsX, I560M,
608 13
559 13 L559F, L559H,
564 14 L564L,
571 14 I571V, I571L,
567 14 I567M, I567T,
626 14 G626A, G626S, G626V,
555 14
628 14 G628V, G628R, G628A, G628D, G628Del, G628S,
652 14 Y652X,
623 15 T623I,
651 15 M651K,
556 15
566 15 C566G, C566S, C566R, C566F, C566S,
568 15 W568C, W568C,