KCNH2 Variant G626R Detail

We estimate the penetrance of LQTS for KCNH2 G626R is 85%. We are unaware of any observations of this variant in individuals. G626R is not present in gnomAD. G626R 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G626R around 85% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.734 0.994 -3 0.969 91
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 2 8 -
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.

G626R has 92 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
626 0 G626A, G626S, G626V,
625 4 V625E,
627 4 F627X, F627L, F627fsX, F627L, F627L,
626 5 G626A, G626S, G626V,
626 5 G626A, G626S, G626V,
620 5 S620I, S620G,
625 5 V625E,
627 5 F627X, F627L, F627fsX, F627L, F627L,
628 6 G628V, G628R, G628A, G628D, G628Del, G628S,
624 7 S624R, S624R, S624R, S624N,
621 7 S621N, S621R, S621R, S621R,
626 7 G626A, G626S, G626V,
625 7 V625E,
624 8 S624R, S624R, S624R, S624N,
625 8 V625E,
617 8 F617V, F617L, F617L, F617L,
628 8 G628V, G628R, G628A, G628D, G628Del, G628S,
623 8 T623I,
630 8 V630I, V630T, V630A,
628 8 G628V, G628R, G628A, G628D, G628Del, G628S,
624 9 S624R, S624R, S624R, S624N,
616 9 Y616S,
627 9 F627X, F627L, F627fsX, F627L, F627L,
629 9 N629K, N629S, N629K, N629I, N629D, N629T,
621 9 S621N, S621R, S621R, S621R,
620 9 S620I, S620G,
620 9 S620I, S620G,
631 9 S631F,
645 9 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
627 9 F627X, F627L, F627fsX, F627L, F627L,
624 9 S624R, S624R, S624R, S624N,
631 10 S631F,
628 10 G628V, G628R, G628A, G628D, G628Del, G628S,
622 10 L622F,
629 10 N629K, N629S, N629K, N629I, N629D, N629T,
641 10 S641F, S641P,
632 10 P632S, P632A,
618 11 T618S, T618S,
645 11 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
623 11 T623I,
619 11
632 11 P632S, P632A,
641 11 S641F, S641P,
630 11 V630I, V630T, V630A,
623 11 T623I,
617 11 F617V, F617L, F617L, F617L,
621 11 S621N, S621R, S621R, S621R,
616 12 Y616S,
629 12 N629K, N629S, N629K, N629I, N629D, N629T,
620 12 S620I, S620G,
630 12 V630I, V630T, V630A,
644 12 V644F, V644I,
642 12 I642Del, I642V,
638 12 K638Del, K638E, K638D, K638R,
622 12 L622F,
621 13 S621N, S621R, S621R, S621R,
644 13 V644F, V644I,
613 13 T613A, T613L, T613K, T613M,
617 13 F617V, F617L, F617L, F617L,
623 13 T623I,
631 13 S631F,
629 13 N629K, N629S, N629K, N629I, N629D, N629T,
614 13 A614T, A614V,
616 13 Y616S,
615 13 L615V, L615F,
648 13 G648A,
618 14 T618S, T618S,
631 14 S631F,
645 14 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
652 14 Y652X,
633 14 N633D, N633I, N633S,
568 14 W568C, W568C,
648 14 G648A,
622 14 L622F,
642 14 I642Del, I642V,
630 14 V630I, V630T, V630A,
619 14
649 14
638 14 K638Del, K638E, K638D, K638R,
640 14 F640L, F640V, F640L, F640L, F640Del,
633 15 N633D, N633I, N633S,
645 15 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
649 15
619 15
640 15 F640L, F640V, F640L, F640L, F640Del,
585 15 W585C, W585C,
646 15
637 15 E637G, E637X, E637K,
632 15 P632S, P632A,
637 15 E637G, E637X, E637K,
618 15 T618S, T618S,
652 15 Y652X,