KCNH2 Variant L751R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L751R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L751R has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 98% 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.836 1.0 -2 0.959 9

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 L751R.
Neighbour residue Distance (Å) Observed variants
751 0 L751V,
750 5 C750X,
749 5
754 6
737 6 L737P,
748 6
752 6 R752P, R752Q, R752W,
753 6 A753S,
747 6
746 7 A746S, A746X,
730 7
755 7
743 7
726 9
745 9 G745X, G745A,
733 9
848 9
845 10
729 10
738 10 Q738X,
736 10
756 10 M756V,
758 10
841 10 V841L, V841L
742 11
727 11
773 11
774 11 D774Y, D774X,
744 11 R744G, R744fsX, R744X, R744P, R744Q,
771 11 H771R, H771fsX,
772 11
757 11
740 12 C740G, C740W,
852 12
735 12 S735L,
842 12
734 12 R734C, R734H,
732 12
731 13 H731R,
838 13 L838R,
728 13
851 13
723 13 C723X, C723R, C723G,
739 13 H739fsX,
775 13
844 13 M844V,
725 14 Q725fsX, Q725R,
849 14
781 14
722 14
833 14
831 14
847 14
817 14
724 14 L724X,
770 14
741 15 K741R,
846 15 P846S, P846T,
818 15 S818A, S818W, S818L,
821 15 D821E, D821E,
837 15 D837G, D837Y, D837N,
768 15