KCNH2 Variant V644I

Summary of observed carriers, functional annotations, and structural context for KCNH2 V644I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

2/19 effective observations

Total carriers

9

0 LQT2 · 4 unaffected

Functional studies

0

Publications with functional data

V644I is present in 9 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 183% of WT with a standard error of 0%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.891 0.574 3 0.742 68

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
Literature, cohort, and gnomAD – 9 4 0 –
Variant features alone – 10 8 2 –

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 V644I.
Neighbour residue Distance (Å) Observed variants
644 0 V644F, V644I,
643 4
645 5 M645L, M645L, M645I, M645R, M645I, M645V, M645I,
641 5 S641P, S641F,
647 5
621 5 S621R, S621N, S621R, S621R,
640 6 F640L, F640Del, F640L, F640L, F640V
622 6 L622F,
648 6 G648A,
642 6 I642V, I642Del,
646 7
618 7 T618S, T618S,
564 7 L564L,
649 8
617 8 F617V, F617L, F617L, F617L,
620 9 S620I, S620G,
561 9 A561P, A561V, A561T,
639 9 I639F, I639N,
560 10 I560fsX, I560M,
619 10
568 10 W568C, W568C,
623 10 T623I,
651 10 M651K,
623 10 T623I,
625 10 V625E,
567 10 I567M, I567T,
619 10
650 10 L650X,
624 10 S624N, S624R, S624R, S624R,
627 11 F627L, F627L, F627X, F627L, F627fsX,
565 11
616 11 Y616S,
620 11 S620I, S620G,
638 11 K638E, K638R, K638D, K638Del,
632 11 P632A, P632S,
637 11 E637X, E637G, E637K,
557 12
652 12 Y652X,
614 12 A614V, A614T,
626 12 G626V, G626S, G626A,
625 12 V625E,
615 12 L615V, L615F,
624 12 S624N, S624R, S624R, S624R,
636 12
563 12 W563G, W563C, W563X, W563C,
626 13 G626V, G626S, G626A,
615 13 L615V, L615F,
571 13 I571L, I571V,
631 13 S631F,
557 13
566 13 C566R, C566G, C566S, C566F, C566S,
630 13 V630A, V630I, V630T,
554 13
622 13 L622F,
558 13 A558P, A558E, A558V,
616 14 Y616S,
562 14 H562Q, H562Q, H562P, H562R,
653 14
652 14 Y652X,
645 14 M645L, M645L, M645I, M645R, M645I, M645V, M645I,
618 14 T618S, T618S,
558 14 A558P, A558E, A558V,
559 14 L559H, L559F,
621 14 S621R, S621N, S621R, S621R,
612 14 V612L, V612L, V612A,
656 14 F656L, F656L, F656L,
655 15
585 15 W585C, W585C,
570 15
627 15 F627L, F627L, F627X, F627L, F627fsX,
634 15 T634I, T634A, T634S, T634P, T634S,
654 15
556 15
617 15 F617V, F617L, F617L, F617L,