G628S Summary

KCNH2 G628S was found in 17 papers (see below) with a total of 19 carriers: 18 had LQT2. G628S is not present in gnomAD. G628S has been functionally characterized in 7 papers. Given the functional data available, we estimate this variant has "Severe Dominant LOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). 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 1 individuals unaffected with LQT2 and 9 individuals affected with LQT2.


G628S Reported Clinical Data

PMID Year Carriers Unaffected LQT2 Other disease
0 2
10973849 2000 1 0 1
11854117 2002 2 0 2
14998624 2004 1 0 1
15840476 2005 2 0 2
16379539 2005 1 0 1
16922724 2006 1 0 1
19996378 2009 2 0 2
23995044 2013 1 0 1
24218437 2013 1 0 1 congenital LQT
26496715 2015 2 0 2
27492745 2016 1 0 1
29650123 2018 1 0
7889573 1995 0 1
Italy Cohort 2020 1 0 1
Japan Cohort 2020 5 1 4
Paris Cohort 2020 1 0 1
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

G628S Reported Functional Data: heterozygously 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).

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
8700910 1996 Xeno
9694858 1998 HEK293
9742063 1998 murine
20947828 2010 murine
21806934 2011 Xeno
22876326 2012 HEK293 15.6

G628S Reported Functional Data: homozygously collected

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
8700910 1996 Xeno 0
9694858 1998 HEK293 0 0
9742063 1998 murine 30
20947828 2010 murine
21806934 2011 Xeno 100 0
22876326 2012 HEK293

G628S Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

PAM Score REVEL Score PROVEAN Score Polyphen2 Score BLAST-PSSM
-2 0.967 -5.801 1 0

G628S has 78 neighbors (found in individuals) within 15 ångströms

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. This results from the fact that the functional Kv11.1 channel 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.

ResidueNumber Distance(Å) Variants
568 13.1 W568C
584 13.1 G584C G584R G584S
584 14 G584C G584R G584S
585 14.5 W585C
585 11.6 W585C
586 14.4 L586M
588 14.9 N588D N588K
588 9.9 N588D N588K
588 12.7 N588D N588K
589 11.5 L589P
590 14.4 G590D G590V
591 13.7 D591H D591N
592 12.9 Q592X
592 14.4 Q592X
592 9.7 Q592X
593 13.9 I593K I593R I593T I593V I593X
612 14.4 V612A V612L
613 10.9 T613A T613K T613L T613M
614 12.6 A614T A614V
615 14.4 L615F L615V
616 14.2 Y616S
616 8.6 Y616S
616 12.3 Y616S
617 12.4 F617L F617V
617 14.5 F617L F617V
617 9.1 F617L F617V
618 13 T618S
619 14.3
620 9.3 S620G S620I
620 12.7 S620G S620I
620 12.5 S620G S620I
621 12.6 S621N S621R
621 11.1 S621N S621R
623 14 T623I
624 14.9 S624N S624R
624 13.6 S624N S624R
624 14.2 S624N S624R
624 12.8 S624N S624R
625 10.5 V625E
625 11.7 V625E
625 12.5 V625E
625 9.5 V625E
626 8.4 G626A G626S G626V
626 6.3 G626A G626S G626V
626 10.1 G626A G626S G626V
626 8.4 G626A G626S G626V
627 10.3 F627fsX F627L F627X
627 11.1 F627fsX F627L F627X
627 5.6 F627fsX F627L F627X
627 6.9 F627fsX F627L F627X
629 11.8 N629D N629I N629K N629S N629T
629 9.8 N629D N629I N629K N629S N629T
629 7.5 N629D N629I N629K N629S N629T
629 3.7 N629D N629I N629K N629S N629T
630 9.4 V630A V630I V630T
630 11 V630A V630I V630T
630 13.7 V630A V630I V630T
630 5 V630A V630I V630T
631 7.1 S631F
631 12 S631F
631 12.7 S631F
631 5.9 S631F
632 14.6 P632A P632S
632 8.4 P632A P632S
632 9.2 P632A P632S
633 11.1 N633D N633I N633S
633 9.7 N633D N633I N633S
634 14.9 T634A T634I T634P T634S
634 13.7 T634A T634I T634P T634S
637 13.2 E637G E637K E637X
637 13.2 E637G E637K E637X
638 13.6 K638D K638Del K638E K638R
638 11.1 K638D K638Del K638E K638R
641 12.9 S641F S641P
641 12.1 S641F S641P
642 14.4 I642Del I642V
645 13.4 M645I M645L M645R M645V
645 14.6 M645I M645L M645R M645V