KCNH2 Variant R694C

Summary of observed carriers, functional annotations, and structural context for KCNH2 R694C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

0/15 effective observations

Total carriers

5

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

R694C is present in 5 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 113% of WT with a standard error of 11%. 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-7.778 0.98 -4 0.884 2

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 – 5 2 0 –
Variant features alone – 10 10 0 –

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 R694C.
Neighbour residue Distance (Å) Observed variants
694 0 R694C, R694H,
698 5 E698K, E698X,
691 6
689 6
684 6
695 6
690 6
693 6 L693X,
697 7 L697X,
692 7
681 9 R681W,
680 9
696 9 R696C, R696H,
5 9
685 10 R685C, R685H, R685P,
699 10 E699D, E699D,
683 10
688 10
677 11 M677T,
687 11
731 11 H731R
728 11
701 12
727 12
702 12
403 12
3 12
724 12 L724X,
682 13 E682X,
6 13 G6R,
700 13
7 13
544 13 E544A, E544fsX,
720 13
686 13
678 13
4 14
732 14
716 14 V716G,