KCNH2 Variant P440S

Summary of observed carriers, functional annotations, and structural context for KCNH2 P440S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

90% CI: 0.3% – 26.1%

0/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

P440S has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 90% 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
0.466 0.09 0 0.573 4

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 10 0 –

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 P440S.
Neighbour residue Distance (Å) Observed variants
440 0 P440L,
439 4
441 4 P441R, P441L,
438 5 E438K, E438X,
442 5
437 7
443 7 T443fsX, T443N,
436 8 T436M,
444 8 E444K, E444D, E444D,
435 8 E435G, E435X,
445 8
434 9
446 9
433 10
447 10 Y447X,
432 11
448 11 A448T, A448S,
431 11 F431L, F431L, F431L,
449 11
430 12
450 12
429 13 A429P, A429V,
451 13 P451L
428 13 S428fsX, S428X, S428L,
452 13
427 14 Y427H, Y427S, Y427C,
453 14
426 14 P426H,
454 14
425 15
455 15