KCNH2 Variant T623I

Summary of observed carriers, functional annotations, and structural context for KCNH2 T623I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

36%

90% CI: 26.7% – 67.8%

7/16 effective observations

Total carriers

6

4 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

T623I is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 6%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.851 0.997 -1 0.958 77

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Japan Cohort 2020 2 0 2
15840476 2005 1 0 1
29766883 2016 2 1 1
Literature, cohort, and gnomAD – 6 1 4 –
Variant features alone – 10 7 3 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that 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 15Å window.

Previously observed variants near T623I.
Neighbour residue Distance (Å) Observed variants
623 0 T623I,
624 4 S624R, S624N, S624R, S624R,
622 5 L622F,
620 5 S620G, S620I,
645 6 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
625 6 V625E,
621 6 S621R, S621N, S621R, S621R,
619 6
652 6 Y652X,
649 7
624 7 S624R, S624N, S624R, S624R,
648 8 G648A,
648 8 G648A,
625 8 V625E,
557 8
626 8 G626S, G626A, G626V,
618 8 T618S, T618S,
646 8
621 9 S621R, S621N, S621R, S621R,
624 9 S624R, S624N, S624R, S624R,
642 10 I642V, I642Del,
656 10 F656L, F656L, F656L,
627 10 F627L, F627fsX, F627X, F627L, F627L,
649 10
644 10 V644I, V644F,
644 10 V644I, V644F,
623 10 T623I,
623 10 T623I,
622 10 L622F,
617 10 F617L, F617V, F617L, F617L,
645 10 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
625 10 V625E,
652 10 Y652X,
641 10 S641P, S641F,
651 10 M651K,
561 10 A561T, A561P, A561V,
624 10 S624R, S624N, S624R, S624R,
616 11 Y616S,
626 11 G626S, G626A, G626V,
647 11
626 11 G626S, G626A, G626V,
650 11 L650X,
653 11
615 11 L615V, L615F,
620 11 S620G, S620I,
647 11
627 12 F627L, F627fsX, F627X, F627L, F627L,
560 12 I560fsX, I560M,
558 12 A558P, A558E, A558V,
655 12
653 12
625 12 V625E,
643 12
652 12 Y652X,
554 12
641 12 S641P, S641F,
620 12 S620G, S620I,
564 13 L564L,
650 13 L650X,
626 13 G626S, G626A, G626V,
651 13 M651K,
646 13
654 14
614 14 A614T, A614V,
630 14 V630I, V630T, V630A,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
618 14 T618S, T618S,
556 14
617 14 F617L, F617V, F617L, F617L,
643 14
565 14
640 14 F640L, F640V, F640Del, F640L, F640L,
623 14 T623I,
638 14 K638E, K638D, K638Del, K638R,
640 14 F640L, F640V, F640Del, F640L, F640L,
621 15 S621R, S621N, S621R, S621R,
657 15 G657S, G657V
622 15 L622F,
656 15 F656L, F656L, F656L,
652 15 Y652X,
627 15 F627L, F627fsX, F627X, F627L, F627L,
632 15 P632A, P632S,
642 15 I642V, I642Del,
659 15
619 15
559 15 L559F, L559H,
639 15 I639F, I639N,
619 15