KCNH2 Variant T473P

Summary of observed carriers, functional annotations, and structural context for KCNH2 T473P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

44%

90% CI: 21.7% – 67.0%

5/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

T473P has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 4%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.56 1.0 -1 0.978 87

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
23010577 2013 2 0 2
Literature, cohort, and gnomAD – 2 0 2 –
Variant features alone – 10 7 3 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
23010577 CHO 0 None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
23010577 CHO 13 1.4 -3.0 None

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 T473P.
Neighbour residue Distance (Å) Observed variants
473 0 T473P,
474 4 T474I,
400 5 I400N,
470 5 N470D,
469 6
472 6 R472C, R472X,
401 7
471 7 F471X,
489 7 I489F, I489I,
402 7 H402R,
407 8
475 8 Y475C, Y475Del,
399 8
484 9
483 9 V483I,
493 9 Y493H, Y493C, Y493F, Y493Ins,
468 9 L468F, L468X, L468R,
466 10 D466E, D466E,
486 10
404 10
485 10 H485X,
398 10 W398L, W398X,
467 10
406 10
490 10 A490T, A490P,
403 11
476 11 V476I,
492 11 H492Y,
410 11 W410X,
482 12 V482A,
411 12
465 12
487 12 G487S, G487R,
538 12
408 12
488 12 R488C, R488H,
537 13 R537W,
405 13
491 13 V491I,
541 13 R541C, R541H,
534 13 R534C,
498 13
477 14
494 14 F494Del,
3 14
501 14 D501N, D501H, D501Y,
481 14
497 14 W497L, W497X,
414 14 I414fsX,
5 14
6 15 G6R
409 15 V409M, V409L, V409L,
480 15 E480V,
464 15 I464X,
496 15