KCNH2 Variant G628S Detail

We estimate the penetrance of LQTS for KCNH2 G628S is 92%. This variant was found in a total of 19 carriers in 17 papers or gnomAD, 18 had LQTS. G628S is not present in gnomAD. G628S has been functionally characterized in 6 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G628S around 92% (26/29).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.801 1.0 0 0.967 97
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
Japan Cohort 2020 5 1 4
Italy Cohort 2020 1 0 1
7889573 1995 None 0 1
11854117 2002 2 0 2
19996378 2009 2 0 2
France Cohort 2020 1 0 1
23995044 2013 1 0 1
10973849 2000 1 0 1
14998624 2004 1 0 1
16379539 2005 1 0 1
15840476 2005 2 0 2
16922724 2006 1 0 1
24218437 2013 1 0 1 congenital LQT
26496715 2015 2 0 2
27492745 2016 1 0 1
29650123 2018 1 0
None 0 2
LITERATURE, COHORT, AND GNOMAD: - 19 1 18 -
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.

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)
8700910 Xeno 0 None None None None
9694858 HEK293 0 0 None None None None
9742063 murine 30 None None None None
20947828 murine None None None None
21806934 Xeno 0 None None None None
22876326 HEK293 None 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)
8700910 Xeno 0 None None None
9694858 HEK293 None None None
9742063 murine None None None
20947828 murine None None None
21806934 Xeno None None None
22876326 HEK293 16 None None None

G628S has 82 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
628 0 G628V, G628R, G628A, G628D, G628Del, G628S,
629 4 N629K, N629S, N629K, N629I, N629D, N629T,
630 5 V630I, V630T, V630A,
627 6 F627X, F627L, F627fsX, F627L, F627L,
631 6 S631F,
626 6 G626A, G626S, G626V,
628 6 G628V, G628R, G628A, G628D, G628Del, G628S,
628 6 G628V, G628R, G628A, G628D, G628Del, G628S,
627 7 F627X, F627L, F627fsX, F627L, F627L,
631 7 S631F,
629 8 N629K, N629S, N629K, N629I, N629D, N629T,
632 8 P632S, P632A,
626 8 G626A, G626S, G626V,
626 8 G626A, G626S, G626V,
616 9 Y616S,
628 9 G628V, G628R, G628A, G628D, G628Del, G628S,
617 9 F617V, F617L, F617L, F617L,
632 9 P632S, P632A,
620 9 S620I, S620G,
630 9 V630I, V630T, V630A,
625 10 V625E,
633 10 N633D, N633I, N633S,
592 10 Q592X,
629 10 N629K, N629S, N629K, N629I, N629D, N629T,
588 10 N588K, N588K, N588D,
626 10 G626A, G626S, G626V,
627 10 F627X, F627L, F627fsX, F627L, F627L,
625 10 V625E,
613 11 T613A, T613L, T613K, T613M,
630 11 V630I, V630T, V630A,
627 11 F627X, F627L, F627fsX, F627L, F627L,
638 11 K638Del, K638E, K638D, K638R,
621 11 S621N, S621R, S621R, S621R,
633 11 N633D, N633I, N633S,
589 12 L589P,
585 12 W585C, W585C,
625 12 V625E,
629 12 N629K, N629S, N629K, N629I, N629D, N629T,
631 12 S631F,
641 12 S641F, S641P,
616 12 Y616S,
617 12 F617V, F617L, F617L, F617L,
625 13 V625E,
620 13 S620I, S620G,
621 13 S621N, S621R, S621R, S621R,
614 13 A614T, A614V,
631 13 S631F,
588 13 N588K, N588K, N588D,
620 13 S620I, S620G,
624 13 S624R, S624R, S624R, S624N,
592 13 Q592X,
641 13 S641F, S641P,
618 13 T618S, T618S,
568 13 W568C, W568C,
584 13 G584C, G584S, G584R,
637 13 E637G, E637X, E637K,
637 13 E637G, E637X, E637K,
645 13 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
638 14 K638Del, K638E, K638D, K638R,
624 14 S624R, S624R, S624R, S624N,
630 14 V630I, V630T, V630A,
634 14 T634S, T634I, T634S, T634P, T634A,
591 14 D591N, D591H,
593 14 I593X, I593V, I593R, I593K, I593T,
623 14 T623I,
584 14 G584C, G584S, G584R,
616 14 Y616S,
624 14 S624R, S624R, S624R, S624N,
619 14
586 14 L586M,
615 14 L615V, L615F,
642 14 I642Del, I642V,
592 14 Q592X,
612 14 V612L, V612A, V612L,
590 14 G590D, G590V,
617 15 F617V, F617L, F617L, F617L,
585 15 W585C, W585C,
632 15 P632S, P632A,
645 15 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
634 15 T634S, T634I, T634S, T634P, T634A,
588 15 N588K, N588K, N588D,
624 15 S624R, S624R, S624R, S624N,