KCNH2 Variant P846T

Summary of observed carriers, functional annotations, and structural context for KCNH2 P846T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

25%

90% CI: 11.6% – 55.6%

3/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

P846T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 58% 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-7.399 0.999 -1 0.924 94

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
Japan Cohort 2020 1 0 1
20975234 2010 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 8 2 –

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)
20975234 CHO 0 None 2.8 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)
20975234 CHO 31 None 19.6 0.846153846

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 P846T.
Neighbour residue Distance (Å) Observed variants
846 0 P846T, P846S,
847 5
849 6
845 6
842 7
848 7
850 7 D850N,
843 7
844 8 M844V,
817 10
841 10 V841L, V841L,
750 10 C750X,
851 10
852 11
747 11
773 12
815 12
839 12
746 12 A746S, A746X,
853 12 W853X,
814 12
816 12 G816V,
775 12
745 12 G745A, G745X,
749 13
840 13 E840Q,
838 13 L838R,
810 14
774 14 D774Y, D774X,
753 14 A753S,
754 14
854 14
818 14 S818A, S818W, S818L,
863 14 R863X, R863P
751 15 L751V,
742 15
772 15