KCNH2 Variant P405A

Summary of observed carriers, functional annotations, and structural context for KCNH2 P405A. 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

P405A 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: 112% of WT with a standard error of 10%. 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 (%)
-7.28 0.944 -1 0.872 14

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 P405A.
Neighbour residue Distance (Å) Observed variants
405 0
404 4
408 6
406 6
409 7 V409M, V409L, V409L,
407 7
403 8
401 8
402 10 H402R,
411 10
400 10 I400N,
541 10 R541C, R541H,
410 10 W410X,
412 12 W412X,
3 12
5 13
474 13 T474I,
473 13 T473P,
413 13 L413P,
544 13 E544A, E544fsX
469 14
399 14
545 14
542 14
414 15 I414fsX,
538 15
691 15