KCNH2 Variant D540Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 D540Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

D540Y has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 73% of WT with a standard error of 18%. 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 (%)
-8.626 1.0 -3 0.933 23

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 D540Y.
Neighbour residue Distance (Å) Observed variants
540 0 D540fsX,
539 4
543 5 S543fsX,
541 5 R541C, R541H,
3 6
542 6
544 7 E544A, E544fsX,
538 7
536 9 A536X,
535 9 V535M,
4 9
674 9 H674Y, H674fsX,
537 10 R537W,
673 10
411 10
545 11
549 11 V549M,
412 11 W412X,
670 11
702 11
408 11
548 11
677 12 M677T,
402 12 H402R,
552 12 L552S,
546 12
476 12 V476I,
407 13
415 13
681 13 R681W,
5 13
698 13 E698K, E698X,
671 13 A671G, A671Del,
705 14 W705fsX, W705X,
534 14 R534C,
533 14
403 14
414 14 I414fsX,
669 14 G669R, G669C, G669X,
547 14 A547T,
678 14
497 14 W497L, W497X,
409 14 V409M, V409L, V409L,
667 14 Y667X,
701 14
404 15
553 15 L553V,
532 15
706 15 S706C, S706F
665 15 R665Q,
675 15
6 15 G6R,