KCNH2 Variant K538E

Summary of observed carriers, functional annotations, and structural context for KCNH2 K538E. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

14%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

K538E has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 49% of WT with a standard error of 11%. 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 (%)
-3.834 0.967 1 0.963 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 K538E.
Neighbour residue Distance (Å) Observed variants
538 0
537 4 R537W,
535 5 V535M,
411 6
536 6 A536X,
542 6
541 7 R541H, R541C,
539 7
534 7 R534C,
540 7 D540fsX,
414 8 I414fsX,
533 8
407 9
415 9
497 9 W497X, W497L,
412 10 W412X,
3 10
408 10
532 10
470 10 N470D,
466 10 D466E, D466E,
410 11 W410X,
543 11 S543fsX,
402 11 H402R,
501 11 D501Y, D501N, D501H,
418 11
544 12 E544A, E544fsX,
413 12 L413P,
473 12 T473P,
409 12 V409M, V409L, V409L,
469 12
493 12 Y493H, Y493C, Y493Ins, Y493F,
463 12 F463L, F463L, F463L,
552 13 L552S,
476 13 V476I,
417 13
531 13 R531Q, R531Del, R531W,
474 13 T474I,
4 13
475 13 Y475Del, Y475C,
467 13
500 13 I500Del,
496 13
416 14
404 14
530 14
406 14
492 14 H492Y,
419 14
548 14
549 14 V549M,
498 14
403 15
545 15
462 15 M462Ins,
401 15
405 15