KCNH2 Variant Y597H

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y597H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

33%

90% CI: 16.9% – 63.2%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y597H 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 16%. 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 (%)
-4.409 0.994 2 0.894 93

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 1 0 1
Literature, cohort, and gnomAD – 1 0 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 Y597H.
Neighbour residue Distance (Å) Observed variants
597 0 Y597H, Y597C,
596 5 P596T, P596S, P596R, P596L,
603 6 G603D,
604 6 G604S, G604C, G604D,
587 6
590 7 G590D, G590V,
605 7 P605L,
586 8 L586M,
595 8 K595E, K595N, K595N,
591 9 D591N, D591H,
576 9
589 10 L589P,
594 10
588 11 N588D, N588K, N588K,
584 11 G584S, G584R, G584C,
593 11 I593V, I593K, I593T, I593R, I593X,
610 11
583 11 I583V,
606 11 S606Del, S606P, S606F,
573 12
577 12
572 12 G572S, G572R, G572C, G572D,
585 12 W585C, W585C,
592 13 Q592X,
607 13
569 14 Y569H, Y569C, Y569X,
609 14 D609N, D609G
575 15 E575K,