KCNH2 Variant S624R

Summary of observed carriers, functional annotations, and structural context for KCNH2 S624R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

33%

3/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

S624R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 85% of WT with a standard error of 19%. 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 (%)
-4.876 0.999 -1 0.955 74

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
29766883 2016 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
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 S624R.
Neighbour residue Distance (Å) Observed variants
624 0 S624R, S624N, S624R, S624R,
625 4 V625E,
623 4 T623I,
625 5 V625E,
624 5 S624R, S624N, S624R, S624R,
624 5 S624R, S624N, S624R, S624R,
621 6 S621R, S621N, S621R, S621R,
620 6 S620G, S620I,
626 7 G626S, G626A, G626V,
623 7 T623I,
624 7 S624R, S624N, S624R, S624R,
622 7 L622F,
652 7 Y652X,
625 8 V625E,
626 8 G626S, G626A, G626V,
625 8 V625E,
645 8 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
626 9 G626S, G626A, G626V,
645 9 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
648 9 G648A,
620 9 S620G, S620I,
623 9 T623I,
627 9 F627L, F627fsX, F627X, F627L, F627L,
649 9
621 9 S621R, S621N, S621R, S621R,
627 9 F627L, F627fsX, F627X, F627L, F627L,
626 9 G626S, G626A, G626V,
649 10
652 10 Y652X,
619 10
652 10 Y652X,
644 10 V644I, V644F,
620 10 S620G, S620I,
623 10 T623I,
621 10 S621R, S621N, S621R, S621R,
648 11 G648A,
618 11 T618S, T618S,
622 11 L622F,
622 11 L622F,
617 11 F617L, F617V, F617L, F617L,
641 12 S641P, S641F,
653 12
652 12 Y652X,
627 12 F627L, F627fsX, F627X, F627L, F627L,
656 12 F656L, F656L, F656L
619 12
627 12 F627L, F627fsX, F627X, F627L, F627L,
616 12 Y616S,
620 12 S620G, S620I,
557 12
651 12 M651K,
647 12
644 12 V644I, V644F,
646 12
641 12 S641P, S641F,
646 12
621 13 S621R, S621N, S621R, S621R,
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
642 13 I642V, I642Del,
648 13 G648A,
653 13
650 13 L650X,
645 13 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
642 13 I642V, I642Del,
656 13 F656L, F656L, F656L
645 13 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
649 13
616 13 Y616S,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
649 14
622 14 L622F,
630 14 V630I, V630T, V630A,
561 14 A561T, A561P, A561V,
647 14
650 14 L650X,
643 14
618 14 T618S, T618S,
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
617 14 F617L, F617V, F617L, F617L,
617 14 F617L, F617V, F617L, F617L,
653 14
655 14
615 14 L615V, L615F,
648 14 G648A,
631 14 S631F,
618 15 T618S, T618S,
619 15
557 15
640 15 F640L, F640V, F640Del, F640L, F640L,
564 15 L564L,
560 15 I560fsX, I560M,
632 15 P632A, P632S,
629 15 N629D, N629T, N629S, N629I, N629K, N629K,
628 15 G628S, G628R, G628Del, G628D, G628A, G628V,
651 15 M651K,
654 15