KCNH2 Variant C643G Detail

We estimate the penetrance of LQTS for KCNH2 C643G is 76%. We are unaware of any observations of this variant in individuals. C643G is not present in gnomAD. C643G 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 C643G around 76% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-11.601 0.98 -3 0.818 77
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.

C643G has 56 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
643 0
644 4 V644F, V644I,
642 5 I642Del, I642V,
640 5 F640L, F640V, F640L, F640L, F640Del,
646 6
647 6
641 6 S641F, S641P,
645 7 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
639 7 I639F, I639N,
648 9 G648A,
564 9 L564L,
619 9
621 10 S621N, S621R, S621R, S621R,
649 10
622 10 L622F,
567 10 I567M, I567T,
618 11 T618S, T618S,
638 11 K638Del, K638E, K638D, K638R,
636 11
650 11 L650X,
616 11 Y616S,
615 11 L615V, L615F,
568 11 W568C, W568C,
637 12 E637G, E637X, E637K,
560 12 I560fsX, I560M,
651 12 M651K,
554 12
617 12 F617V, F617L, F617L, F617L,
623 12 T623I,
558 12 A558V, A558P, A558E,
557 12
561 12 A561V, A561P, A561T,
571 12 I571V, I571L,
612 12 V612L, V612A, V612L,
620 12 S620I, S620G,
632 12 P632S, P632A,
565 13
627 13 F627X, F627L, F627fsX, F627L, F627L,
625 13 V625E,
635 13 N635I,
563 13 W563X, W563C, W563G, W563C,
620 13 S620I, S620G,
561 14 A561V, A561P, A561T,
618 14 T618S, T618S,
624 14 S624R, S624R, S624R, S624N,
623 14 T623I,
634 14 T634S, T634I, T634S, T634P, T634A,
622 14 L622F,
566 14 C566G, C566S, C566R, C566F, C566S,
619 14
570 14
611 15 Y611D,
555 15
613 15 T613A, T613L, T613K, T613M,
652 15 Y652X,
614 15 A614T, A614V,