KCNH2 Variant S621R

Summary of observed carriers, functional annotations, and structural context for KCNH2 S621R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

36%

4/12 effective observations

Total carriers

2

1 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

S621R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 30% of WT with a standard error of 27%. 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 (%)
-4.876 0.999 -1 0.974 75

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
20167303 2010 2 1 1
Literature, cohort, and gnomAD – 2 1 1 –
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 S621R.
Neighbour residue Distance (Å) Observed variants
621 0 S621R, S621R, S621N, S621R,
620 4 S620G, S620I,
622 5 L622F,
618 5 T618S, T618S,
644 5 V644F, V644I,
617 6 F617L, F617L, F617L, F617V,
645 6 M645L, M645L, M645I, M645R, M645I, M645V, M645I,
623 6 T623I,
624 6 S624N, S624R, S624R, S624R,
625 6 V625E,
641 7 S641P, S641F,
626 7 G626V, G626S, G626A,
625 7 V625E,
627 7 F627L, F627fsX, F627X, F627L, F627L,
619 7
648 8 G648A,
626 9 G626V, G626S, G626A,
640 9 F640Del, F640L, F640V, F640L, F640L,
623 9 T623I,
620 9 S620G, S620I,
564 9 L564L,
616 9 Y616S,
624 9 S624N, S624R, S624R, S624R,
627 9 F627L, F627fsX, F627X, F627L, F627L,
645 9 M645L, M645L, M645I, M645R, M645I, M645V, M645I,
642 10 I642Del, I642V,
647 10
561 10 A561P, A561V, A561T,
643 10
649 10
630 10 V630A, V630T, V630I,
568 10 W568C, W568C,
632 10 P632S, P632A,
615 10 L615F, L615V,
652 10 Y652X,
646 10
624 10 S624N, S624R, S624R, S624R,
631 11 S631F,
616 11 Y616S,
614 11 A614V, A614T,
565 11
628 11 G628S, G628V, G628D, G628Del, G628A, G628R,
619 11
557 11
626 11 G626V, G626S, G626A,
560 11 I560M, I560fsX,
642 12 I642Del, I642V,
651 12 M651K,
625 12 V625E,
638 12 K638E, K638D, K638R, K638Del,
625 12 V625E,
637 12 E637X, E637K, E637G,
641 12 S641P, S641F,
613 12 T613M, T613L, T613A, T613K,
621 13 S621R, S621R, S621N, S621R,
621 13 S621R, S621R, S621N, S621R,
628 13 G628S, G628V, G628D, G628Del, G628A, G628R,
626 13 G626V, G626S, G626A,
624 13 S624N, S624R, S624R, S624R,
649 13
629 13 N629K, N629D, N629T, N629I, N629S, N629K,
629 13 N629K, N629D, N629T, N629I, N629S, N629K,
639 13 I639N, I639F,
650 13 L650X,
622 13 L622F,
567 13 I567M, I567T,
646 13
558 13 A558V, A558E, A558P,
652 13 Y652X,
585 14 W585C, W585C,
617 14 F617L, F617L, F617L, F617V,
638 14 K638E, K638D, K638R, K638Del,
627 14 F627L, F627fsX, F627X, F627L, F627L,
653 14
648 14 G648A,
562 14 H562R, H562Q, H562P, H562Q,
644 14 V644F, V644I,
618 14 T618S, T618S,
620 14 S620G, S620I,
632 14 P632S, P632A,
656 14 F656L, F656L, F656L,
612 14 V612L, V612L, V612A,
566 14 C566S, C566F, C566R, C566S, C566G,
623 15 T623I,
630 15 V630A, V630T, V630I,
615 15 L615F, L615V,
636 15
633 15 N633S, N633D, N633I,
563 15 W563X, W563G, W563C, W563C,
571 15 I571V, I571L,