KCNH2 Variant V423G

Summary of observed carriers, functional annotations, and structural context for KCNH2 V423G. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

30%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V423G has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 0%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-6.662 0.983 -4 0.93 73

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 7 3 –

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 V423G.
Neighbour residue Distance (Å) Observed variants
423 0
422 4 A422T,
424 4
562 6 H562P, H562R, H562Q, H562Q,
420 6 Y420C,
426 6 P426H,
421 6 T421fsX, T421M,
425 6
419 6
559 7 L559F, L559H,
427 7 Y427H, Y427S, Y427C,
563 8 W563G, W563C, W563C, W563X,
418 9
558 9 A558P, A558E, A558V,
428 9 S428fsX, S428X, S428L,
566 10 C566S, C566R, C566G, C566S, C566F,
529 10
611 10 Y611D,
561 10 A561T, A561P, A561V,
555 11
417 11
528 11 R528W, R528X, R528P,
416 11
560 11 I560fsX, I560M,
565 11
429 11 A429P, A429V,
556 11
532 11
456 11 D456Y,
431 12 F431L, F431L, F431L,
452 12
430 12
615 12 L615V, L615F,
531 12 R531W, R531Del, R531Q,
526 12
564 12 L564L,
415 12
459 13
525 13 K525N, K525N,
455 13
567 13 I567T, I567M,
557 14
527 14
432 14
612 14 V612L, V612L, V612A,
614 14 A614T, A614V,
530 14
551 14 F551L, F551L, F551L,
619 14
552 14 L552S,
453 15
618 15 T618S, T618S
414 15 I414fsX,
608 15
460 15 D460fsX,
569 15 Y569H, Y569C, Y569X,