KCNH2 Variant H731R

Summary of observed carriers, functional annotations, and structural context for KCNH2 H731R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

14%

2/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

H731R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 10% 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 (%)
-7.848 0.969 0 0.928 75

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
Literature, cohort, and gnomAD – 1 0 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 H731R.
Neighbour residue Distance (Å) Observed variants
731 0 H731R,
732 4
734 5 R734C, R734H,
730 6
728 6
689 6
690 7
733 7
687 7
729 7
727 7
693 8 L693X,
688 8
735 9 S735L,
726 10
738 10 Q738X,
692 10
684 10
683 10
737 10 L737P,
755 11
686 11
736 11
694 11 R694C, R694H,
691 11
724 12 L724X,
697 12 L697X,
752 12 R752W, R752Q, R752P,
760 12
725 12 Q725fsX, Q725R,
696 12 R696C, R696H,
831 12
751 13 L751V,
717 13 L717P,
758 13
756 13 M756V,
739 13 H739fsX,
713 13 M713V,
783 14 S783P,
720 14
695 14
829 14 D829A, D829E, D829E
784 14 R784G, R784W, R784Q,
754 14
685 14 R685C, R685H, R685P,
680 14
723 14 C723R, C723G, C723X,
716 14 V716G,
759 14 K759N, K759N,
748 15
707 15
753 15 A753S,