KCNH2 Variant Y420N

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y420N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

23%

90% CI: 5.8% – 47.1%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y420N 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-8.565 0.998 -2 0.962 93

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 8 2 –

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 Y420N.
Neighbour residue Distance (Å) Observed variants
420 0 Y420C,
424 5
421 5 T421fsX, T421M,
423 6
417 6
456 7 D456Y,
419 7
459 7
422 7 A422T,
418 7
455 7
425 8
416 8
452 9
528 9 R528W, R528X, R528P,
531 9 R531W, R531Del, R531Q,
458 10
460 10 D460fsX,
426 10 P426H,
428 10 S428fsX, S428X, S428L,
453 10
427 11 Y427H, Y427S, Y427C,
463 11 F463L, F463L, F463L,
457 11 L457P,
415 11
529 11
414 11 I414fsX,
454 11
462 12 M462Ins,
413 12 L413P,
559 12 L559F, L559H,
562 12 H562P, H562R, H562Q, H562Q,
525 12 K525N, K525N,
532 12
451 12 P451L,
563 13 W563G, W563C, W563C, W563X,
461 13
429 13 A429P, A429V,
527 13
526 13
504 13 A504V,
555 14
530 14
534 14 R534C,
558 14 A558P, A558E, A558V,
450 14
535 15 V535M,
566 15 C566S, C566R, C566G, C566S, C566F