KCNH2 Variant Y545F

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y545F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y545F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 135% of WT with a standard error of %. 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 (%)
-3.6 0.73 3 0.817 45

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 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 Y545F.
Neighbour residue Distance (Å) Observed variants
545 0
544 5 E544A, E544fsX,
546 6
548 6
547 7 A547T,
543 7 S543fsX,
549 9 V549M,
412 9 W412X,
681 9 R681W,
542 9
541 9 R541C, R541H,
540 11 D540fsX,
678 11
666 11
408 11
550 11
3 11
551 12 F551L, F551L, F551L,
685 12 R685C, R685H, R685P,
674 12 H674Y, H674fsX,
665 12 R665Q,
552 12 L552S,
677 12 M677T,
409 12 V409M, V409L, V409L,
539 12
662 12
411 13
682 13 E682X,
415 14
405 14
553 14 L553V,
673 15
680 15
538 15
675 15
667 15 Y667X,
684 15
698 15 E698K, E698X