KCNH2 Variant R20L

Summary of observed carriers, functional annotations, and structural context for KCNH2 R20L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

90% CI: 4.0% – 36.6%

2/13 effective observations

Total carriers

3

1 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

R20L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 75% of WT with a standard error of 12%. 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 (%)
-3.959 0.025 -3 0.835 63

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 3 2 1
Literature, cohort, and gnomAD – 3 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 R20L.
Neighbour residue Distance (Å) Observed variants
20 0 R20G, R20L,
16 6 D16A,
17 6
19 7 I19F,
23 7
21 7
24 8
18 8 I18M,
22 9 F22Y, F22S,
785 10 G785S, G785fsX, G785D,
786 10
826 10 T826A, T826I,
15 11 L15V,
13 11 T13N,
25 11 Q25P,
801 11 K801T,
825 12
479 12
14 12
784 12 R784G, R784W, R784Q,
800 12
26 13 S26I,
43 13 Y43D, Y43C,
27 13 R27X, R27P,
29 13 F29L, F29V, F29S, F29L, F29L
827 13
45 13 N45D, N45K, N45K,
798 13 I798fsX,
828 13
480 14 E480V,
787 15
46 15 D46Y, D46E, D46E,