KCNH2 Variant R685C

Summary of observed carriers, functional annotations, and structural context for KCNH2 R685C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

1/15 effective observations

Total carriers

5

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

R685C is present in 5 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 5% of WT with a standard error of 5%. 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 (%)
-7.775 1.0 -4 0.914 32

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 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 R685C.
Neighbour residue Distance (Å) Observed variants
685 0 R685P, R685H, R685C,
684 6
682 6 E682X,
681 7 R681W,
688 8
686 8
683 9
680 9
689 9
687 9
678 9
694 10 R694H, R694C,
709 10
545 12
677 12 M677T,
711 12 I711V,
708 12
690 12
544 12 E544A, E544fsX,
698 13 E698K, E698X,
679 13 R679Q, R679W,
707 13
710 13
691 13
697 13 L697X,
713 13 M713V,
546 14
666 14
706 14 S706C, S706F,
693 14 L693X,
731 14 H731R,
716 15 V716G,
669 15 G669X, G669R, G669C,
668 15 S668L,
705 15 W705fsX, W705X,
675 15