KCNH2 Variant L553V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L553V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

90% CI: 5.3% – 41.5%

2/12 effective observations

Total carriers

2

1 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

L553V has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 86% of WT with a standard error of 13%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.873 0.985 1 0.914 43

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
France Cohort 2020 2 1 1
Literature, cohort, and gnomAD – 2 1 1 –
Variant features alone – 10 9 1 –

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 L553V.
Neighbour residue Distance (Å) Observed variants
553 0 L553V,
552 5 L552S,
655 5
554 6
550 6
556 6
549 6 V549M,
555 7
659 7
658 7
551 7 F551L, F551L, F551L,
656 8 F656L, F656L, F656L,
557 8
548 9
662 9
654 9
651 9 M651K,
657 9 G657S, G657V,
547 10 A547T,
558 10 A558P, A558E, A558V,
546 11
660 11 S660L,
560 11 I560fsX, I560M,
650 11 L650X,
559 11 L559F, L559H,
543 11 S543fsX,
661 11 A661V,
539 11
653 12
663 12
652 12 Y652X,
649 12
542 12
646 12
535 13 V535M,
665 13 R665Q,
415 13
653 13
419 13
536 13 A536X,
650 14 L650X,
561 14 A561T, A561P, A561V,
663 14
532 14
654 14
666 14
648 14 G648A,
622 14 L622F,
667 14 Y667X,
664 14 Q664X,
674 14 H674Y, H674fsX
545 14
660 14 S660L,
619 14
540 15 D540fsX,
412 15 W412X,
647 15
563 15 W563G, W563C, W563C, W563X,
648 15 G648A,
647 15
670 15
671 15 A671G, A671Del,