KCNH2 Variant L401P

Summary of observed carriers, functional annotations, and structural context for KCNH2 L401P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

90% CI: 2.5% – 38.0%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L401P has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 62% 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 (%)
-6.653 0.415 -3 0.929 80

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 L401P.
Neighbour residue Distance (Å) Observed variants
401 0
400 4 I400N,
404 5
403 5
402 5 H402R,
474 6 T474I,
473 7 T473P,
399 7
407 8
405 8
406 9
484 9
5 10
482 10 V482A,
483 10 V483I,
408 10
398 11 W398L, W398X,
472 11 R472C, R472X,
469 11
475 11 Y475C, Y475Del,
485 12 H485X,
476 12 V476I,
6 12 G6R
470 12 N470D,
3 12
489 12 I489F, I489I,
541 13 R541C, R541H,
8 13
411 13
410 13 W410X,
481 13
409 13 V409M, V409L, V409L,
471 14 F471X,
486 14
4 14
7 14
695 15
466 15 D466E, D466E,
538 15