KCNH2 Variant R5M

Summary of observed carriers, functional annotations, and structural context for KCNH2 R5M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

R5M 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: 87% of WT with a standard error of 18%. 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 (%)
-3.182 0.749 -2 0.883 29

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 R5M.
Neighbour residue Distance (Å) Observed variants
5 0
6 5 G6R,
403 6
695 6
698 7 E698X, E698K,
699 7 E699D, E699D,
4 7
3 7
402 7 H402R,
7 8
481 9
482 9 V482A,
476 9 V476I,
8 9
702 9
694 9 R694C, R694H,
401 10
404 10
691 11
474 11 T474I,
696 11 R696C, R696H,
697 11 L697X,
692 11
541 12 R541H, R541C,
480 12 E480V,
483 12 V483I,
475 12 Y475Del, Y475C,
693 13 L693X,
9 13 A9V, A9T,
405 13
703 13
765 13
701 13
544 13 E544fsX, E544A,
540 13 D540fsX,
477 13
700 13
478 13 A478D,
408 13
681 13 R681W,
677 14 M677T,
407 14
766 14
764 14
690 14
484 14
473 14 T473P,
400 14 I400N
680 15
684 15
689 15
10 15
767 15 D767X,