KCNH2 Variant M645L

Summary of observed carriers, functional annotations, and structural context for KCNH2 M645L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

43%

5/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

M645L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 24% 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 (%)
-2.9 0.88 2 0.945 76

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
19038855 2009 1 0 1 Seizure
10973849 2000 1 0 1
Literature, cohort, and gnomAD – 2 0 2 –
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 M645L.
Neighbour residue Distance (Å) Observed variants
645 0 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
644 5 V644I, V644F,
642 5 I642V, I642Del,
641 5 S641P, S641F,
619 5
623 6 T623I,
646 6
621 6 S621R, S621N, S621R, S621R,
620 6 S620G, S620I,
643 7
648 7 G648A,
625 7 V625E,
649 7
616 8 Y616S,
647 8
622 8 L622F,
627 8 F627L, F627fsX, F627X, F627L, F627L,
624 8 S624R, S624N, S624R, S624R,
624 9 S624R, S624N, S624R, S624R,
640 9 F640L, F640V, F640Del, F640L, F640L,
622 9 L622F,
626 9 G626S, G626A, G626V,
621 9 S621R, S621N, S621R, S621R,
615 9 L615V, L615F,
618 9 T618S, T618S,
620 10 S620G, S620I,
557 10
639 10 I639F, I639N,
623 10 T623I,
618 10 T618S, T618S,
638 10 K638E, K638D, K638Del, K638R,
617 10 F617L, F617V, F617L, F617L,
626 11 G626S, G626A, G626V,
617 11 F617L, F617V, F617L, F617L,
650 11 L650X,
652 11 Y652X,
632 11 P632A, P632S,
625 11 V625E,
561 11 A561T, A561P, A561V,
558 11 A558P, A558E, A558V,
652 12 Y652X,
564 12 L564L,
651 12 M651K,
625 12 V625E,
554 12
612 12 V612L, V612L, V612A,
656 12 F656L, F656L, F656L
614 12 A614T, A614V,
637 13 E637K, E637G, E637X,
631 13 S631F,
613 13 T613A, T613L, T613K, T613M,
619 13
568 13 W568C, W568C,
648 13 G648A,
624 13 S624R, S624N, S624R, S624R,
629 13 N629D, N629T, N629S, N629I, N629K, N629K,
630 13 V630I, V630T, V630A,
624 13 S624R, S624N, S624R, S624R,
653 13
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
561 14 A561T, A561P, A561V,
560 14 I560fsX, I560M,
636 14
626 14 G626S, G626A, G626V,
627 14 F627L, F627fsX, F627X, F627L, F627L,
560 14 I560fsX, I560M,
630 14 V630I, V630T, V630A,
644 14 V644I, V644F,
627 14 F627L, F627fsX, F627X, F627L, F627L,
565 14
564 14 L564L,
651 15 M651K,
626 15 G626S, G626A, G626V,
557 15
628 15 G628S, G628R, G628Del, G628D, G628A, G628V,
611 15 Y611D,
562 15 H562P, H562R, H562Q, H562Q,
625 15 V625E,
567 15 I567T, I567M,
565 15
645 15 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
645 15 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
635 15 N635I,
655 15