KCNH2 Variant C555F

Summary of observed carriers, functional annotations, and structural context for KCNH2 C555F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

90% CI: 4.9% – 44.9%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

C555F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 94% of WT with a standard error of 20%. 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 (%)
-10.243 0.41 -2 0.847 44

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 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 C555F.
Neighbour residue Distance (Å) Observed variants
555 0
556 4
552 5 L552S,
551 5 F551L, F551L, F551L,
554 6
558 6 A558P, A558E, A558V,
559 6 L559F, L559H,
553 7 L553V,
419 7
557 7
550 9
560 9 I560fsX, I560M,
415 9
549 10 V549M,
548 10
422 10 A422T,
655 10
423 11
561 11 A561T, A561P, A561V,
416 11
418 11
646 11
562 11 H562P, H562R, H562Q, H562Q,
563 11 W563G, W563C, W563C, W563X,
532 11
535 12 V535M,
656 12 F656L, F656L, F656L
542 12
547 12 A547T,
651 12 M651K,
659 12
619 12
421 13 T421fsX, T421M,
412 13 W412X,
650 13 L650X,
649 13
539 14
417 14
420 14 Y420C,
658 14
546 14
536 14 A536X,
615 14 L615V, L615F,
543 14 S543fsX,
622 14 L622F,
424 14
642 14 I642V, I642Del,
414 14 I414fsX,
564 15 L564L,
647 15
654 15
662 15
643 15
529 15
652 15 Y652X,