KCNH2 Variant T399P

Summary of observed carriers, functional annotations, and structural context for KCNH2 T399P. 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

T399P 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: 0% of WT with a standard error of 6%. 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 (%)
-5.527 0.121 -1 0.95 39

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 T399P.
Neighbour residue Distance (Å) Observed variants
399 0
398 4 W398L, W398X,
400 4 I400N,
472 7 R472C, R472X,
401 7
485 8 H485X,
473 8 T473P,
484 8
474 9 T474I,
486 10
469 11
404 11
406 12
483 12 V483I,
489 12 I489F, I489I
402 12 H402R,
403 12
471 12 F471X,
407 12
470 13 N470D,
468 13 L468F, L468X, L468R,
482 13 V482A,
475 13 Y475C, Y475Del,
487 13 G487S, G487R,
488 14 R488C, R488H,
405 14