KCNH2 Variant L622F

Summary of observed carriers, functional annotations, and structural context for KCNH2 L622F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

31%

90% CI: 28.3% – 67.2%

8/17 effective observations

Total carriers

7

5 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

L622F has not been reported 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 17%. 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 (%)
-3.9 0.989 0 0.957 73

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 1 1
France Cohort 2020 4 1 3
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 7 2 5 –
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 L622F.
Neighbour residue Distance (Å) Observed variants
622 0 L622F,
623 5 T623I,
621 5 S621R, S621N, S621R, S621R,
648 5 G648A,
619 6
618 6 T618S, T618S,
644 6 V644I, V644F,
620 6 S620G, S620I,
624 7 S624R, S624N, S624R, S624R,
557 7
652 7 Y652X,
561 7 A561T, A561P, A561V,
647 7
651 8 M651K,
645 8 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
560 8 I560fsX, I560M,
649 8
564 9 L564L,
617 9 F617L, F617V, F617L, F617L,
645 9 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
625 9 V625E,
625 9 V625E,
641 10 S641P, S641F,
558 10 A558P, A558E, A558V,
649 10
615 10 L615V, L615F,
623 10 T623I,
646 10
650 10 L650X,
643 10
626 10 G626S, G626A, G626V,
656 10 F656L, F656L, F656L,
646 10
640 11 F640L, F640V, F640Del, F640L, F640L,
655 11
653 11
624 11 S624R, S624N, S624R, S624R,
642 11 I642V, I642Del,
624 11 S624R, S624N, S624R, S624R,
616 11 Y616S,
565 11
627 12 F627L, F627fsX, F627X, F627L, F627L,
556 12
642 12 I642V, I642Del,
614 12 A614T, A614V,
559 12 L559F, L559H,
648 12 G648A,
627 12 F627L, F627fsX, F627X, F627L, F627L,
554 12
654 12
562 12 H562P, H562R, H562Q, H562Q,
620 12 S620G, S620I,
626 12 G626S, G626A, G626V,
568 13 W568C, W568C,
563 13 W563G, W563C, W563C, W563X,
652 13 Y652X,
641 13 S641P, S641F,
621 13 S621R, S621N, S621R, S621R,
619 13
567 13 I567T, I567M,
644 13 V644I, V644F,
630 14 V630I, V630T, V630A,
650 14 L650X,
624 14 S624R, S624N, S624R, S624R,
656 14 F656L, F656L, F656L,
625 14 V625E,
626 14 G626S, G626A, G626V,
652 14 Y652X,
553 14 L553V,
555 14
566 14 C566S, C566R, C566G, C566S, C566F,
647 14
643 14
625 14 V625E,
613 14 T613A, T613L, T613K, T613M,
616 14 Y616S,
653 15
632 15 P632A, P632S,
623 15 T623I,
622 15 L622F,
622 15 L622F,
631 15 S631F,
657 15 G657S, G657V