KCNH2 Variant I639T Detail

We estimate the penetrance of LQTS for KCNH2 I639T is 75%. We are unaware of any observations of this variant in individuals. I639T is not present in gnomAD. I639T has not been functionally characterized. 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 I639T around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.362 0.867 -1 0.949 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.

I639T 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 K638E, K638R, K638D, K638Del,
640 6 F640Del, F640L, F640L, F640L, F640V,
641 6 S641P, S641F,
635 7 N635I,
612 7 V612A, V612L, V612L,
643 7
637 7 E637X, E637K, E637G,
616 8 Y616S,
634 9 T634P, T634S, T634I, T634S, T634A,
615 9 L615F, L615V,
632 9 P632S, P632A,
644 9 V644F, V644I,
608 10
613 10 T613K, T613M, T613L, T613A,
571 10 I571L, I571V,
645 10 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
611 10 Y611D,
609 10 D609G, D609N,
619 11
568 11 W568C, W568C,
646 11
614 11 A614T, A614V,
633 11 N633S, N633I, N633D,
567 12 I567T, I567M,
575 12 E575K,
647 13
564 13 L564L,
627 13 F627L, F627L, F627fsX, F627X, F627L,
621 13 S621R, S621R, S621R, S621N,
620 13 S620G, S620I,
631 13 S631F,
617 13 F617L, F617L, F617V, F617L,
618 13 T618S, T618S,
570 13
558 13 A558P, A558V, A558E,
572 14 G572S, G572C, G572R, G572D,
617 14 F617L, F617L, F617V, F617L,
562 14 H562P, H562Q, H562Q, H562R,
629 14 N629K, N629I, N629T, N629S, N629K, N629D,
561 14 A561V, A561T, A561P,
585 14 W585C, W585C,
610 14
565 14
618 14 T618S, T618S,
606 14 S606F, S606Del, S606P,
584 14 G584S, G584C, G584R,
607 14
630 15 V630I, V630A, V630T,
648 15 G648A,
623 15 T623I,
593 15 I593K, I593T, I593X, I593R, I593V,