KCNH2 Variant I639A Detail

We estimate the penetrance of LQTS for KCNH2 I639A is 77%. We are unaware of any observations of this variant in individuals. I639A is not present in gnomAD. I639A 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 I639A around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 82
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)
19892743 Xeno 16.2 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)
19892743 Xeno None None None

I639A has 54 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
639 0 I639N, I639F,
636 5
642 5 I642V, I642Del,
638 6 K638R, K638Del, K638D, K638E,
640 6 F640L, F640Del, F640L, F640V, F640L,
641 6 S641P, S641F,
635 7 N635I,
612 7 V612L, V612A, V612L,
643 7
637 7 E637K, E637G, E637X,
616 8 Y616S,
634 9 T634P, T634I, T634S, T634A, T634S,
615 9 L615V, L615F,
632 9 P632A, P632S,
644 9 V644F, V644I,
608 10
613 10 T613A, T613K, T613M, T613L,
571 10 I571V, I571L,
645 10 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
611 10 Y611D,
609 10 D609N, D609G,
619 11
568 11 W568C, W568C,
646 11
614 11 A614V, A614T,
633 11 N633I, N633D, N633S,
567 12 I567M, I567T,
575 12 E575K,
647 13
564 13 L564L,
627 13 F627X, F627L, F627L, F627fsX, F627L,
621 13 S621R, S621R, S621N, S621R,
620 13 S620I, S620G,
631 13 S631F,
617 13 F617V, F617L, F617L, F617L,
618 13 T618S, T618S,
570 13
558 13 A558V, A558P, A558E,
572 14 G572D, G572S, G572R, G572C,
617 14 F617V, F617L, F617L, F617L,
562 14 H562R, H562Q, H562P, H562Q,
629 14 N629T, N629I, N629S, N629D, N629K, N629K,
561 14 A561T, A561V, A561P,
585 14 W585C, W585C,
610 14
565 14
618 14 T618S, T618S,
606 14 S606Del, S606P, S606F,
584 14 G584C, G584R, G584S,
607 14
630 15 V630A, V630I, V630T,
648 15 G648A,
623 15 T623I,
593 15 I593R, I593V, I593T, I593X, I593K,