KCNH2 Variant L737P

Summary of observed carriers, functional annotations, and structural context for KCNH2 L737P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

2/12 effective observations

Total carriers

2

1 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

L737P 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 1%. 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 (%)
-6.809 1.0 -3 0.978 25

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 2 1 1
Literature, cohort, and gnomAD – 2 2 1 –
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 L737P.
Neighbour residue Distance (Å) Observed variants
737 0 L737P,
736 5
743 5
738 5 Q738X,
751 6 L751V,
733 6
735 6 S735L,
740 7 C740G, C740W,
730 7
739 8 H739fsX,
744 8 R744G, R744fsX, R744X, R744Q, R744P,
734 8 R734C, R734H,
754 8
755 8
742 8
746 9 A746S, A746X,
758 9
745 10 G745A, G745X,
750 10 C750X,
781 10
729 10
732 10
748 10
831 10
731 10 H731R,
752 11 R752W, R752Q, R752P,
753 11 A753S,
741 11 K741R,
747 11
749 11
852 12
802 12
726 12
848 12
783 12 S783P,
727 12
756 13 M756V,
856 13
728 13
833 13
757 13
782 13 I782fsX, I782N,
851 13
855 14 S855R, S855R, S855R
804 14
838 14 L838R,
760 14
841 14 V841L, V841L,
759 14 K759N, K759N,
779 14
803 15 D803Y, D803X,
845 15
830 15
832 15
842 15