KCNH2 Variant R4L

Summary of observed carriers, functional annotations, and structural context for KCNH2 R4L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

R4L has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 126% of WT with a standard error of 9%. 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 (%)
-3.652 0.997 -3 0.745 26

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 R4L.
Neighbour residue Distance (Å) Observed variants
4 0
702 5
476 6 V476I,
3 6
6 7 G6R,
5 7
481 8
699 8 E699D, E699D,
478 9 A478D,
698 9 E698K, E698X,
703 9
706 9 S706C, S706F,
402 9 H402R,
540 9 D540fsX,
477 9
482 10 V482A,
701 10
480 10 E480V,
705 11 W705X, W705fsX,
673 11
475 11 Y475Del, Y475C,
403 11
541 11 R541H, R541C,
704 11 A704T, A704V,
7 11
695 12
479 12
677 12 M677T,
474 12 T474I,
700 12
544 12 E544A, E544fsX,
483 12 V483I,
827 13
8 13
539 13
697 13 L697X,
538 13
765 13
764 13
543 13 S543fsX,
674 14 H674Y, H674fsX,
694 14 R694H, R694C,
681 14 R681W,
537 14 R537W,
401 14
707 14
709 14
670 14
696 15 R696C, R696H,
404 15
492 15 H492Y,
708 15
542 15
680 15