KCNH2 Variant L559R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L559R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

32%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L559R 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 5%. 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 (%)
-5.751 1.0 -2 0.976 80

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 – 0 0 0 –
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 L559R.
Neighbour residue Distance (Å) Observed variants
559 0 L559H, L559F,
558 4 A558P, A558E, A558V,
560 5 I560M, I560fsX,
563 5 W563C, W563X, W563G, W563C,
556 5
562 5 H562R, H562P, H562Q, H562Q,
555 6
561 6 A561T, A561P, A561V,
422 6 A422T,
423 7
419 7
557 8
564 9 L564L,
426 10 P426H,
554 10
532 10
421 10 T421fsX, T421M,
552 10 L552S,
565 10
418 10
619 10
566 10 C566G, C566S, C566F, C566R, C566S,
615 10 L615V, L615F,
529 11
553 11 L553V,
424 11
425 11
618 11 T618S, T618S,
551 11 F551L, F551L, F551L,
651 12 M651K,
420 12 Y420C,
611 12 Y611D,
415 12
622 12 L622F,
646 12
567 12 I567M, I567T,
655 13
427 13 Y427S, Y427H, Y427C,
416 13
535 13 V535M,
647 13
642 13 I642V, I642Del,
614 14 A614T, A614V,
417 14
648 14 G648A,
644 14 V644I, V644F,
531 14 R531Del, R531Q, R531W,
550 14
533 14
656 14 F656L, F656L, F656L,
428 15 S428fsX, S428L, S428X,
530 15
526 15
623 15 T623I,
612 15 V612L, V612L, V612A,