KCNH2 Variant G446R

Summary of observed carriers, functional annotations, and structural context for KCNH2 G446R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

G446R 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: 134% of WT with a standard error of 10%. 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 (%)
-5.715 0.999 -2 0.729 39

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 G446R.
Neighbour residue Distance (Å) Observed variants
446 0
445 4
447 4 Y447X,
444 5 E444K, E444D, E444D,
448 5 A448T, A448S,
443 7 T443N, T443fsX,
449 7
442 8
450 8
441 8 P441R, P441L,
451 8 P451L,
440 9 P440L,
452 9
439 10
453 10
438 11 E438K, E438X,
454 11
437 11
455 11
436 12 T436M,
456 12 D456Y,
435 13 E435X, E435G,
457 13 L457P,
434 13
458 13
433 14
459 14
432 14
460 14 D460fsX,
431 15 F431L, F431L, F431L,
461 15