KCNH2 Variant Y493S

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y493S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

32%

3/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y493S 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 (%)
-8.34 1.0 -2 0.986 95

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 Y493S.
Neighbour residue Distance (Å) Observed variants
493 0 Y493H, Y493C, Y493F, Y493Ins,
498 5
494 6 F494Del,
471 6 F471X,
470 6 N470D,
490 6 A490T, A490P,
492 6 H492Y,
496 7
489 7 I489F, I489I,
467 7
497 8 W497L, W497X,
501 8 D501N, D501H, D501Y,
491 8 V491I,
499 9
473 9 T473P,
495 9 K495X,
537 10 R537W
475 10 Y475C, Y475Del,
502 10 M502I, M502I, M502I,
466 10 D466E, D466E,
469 10
468 10 L468F, L468X, L468R,
500 10 I500Del,
534 11 R534C,
474 11 T474I,
472 11 R472C, R472X,
486 12
487 12 G487S, G487R,
538 12
533 13
483 13 V483I,
465 13
503 13
464 13 I464X,
505 13 A505V,
504 13 A504V,
488 13 R488C, R488H,
476 13 V476I,
463 14 F463L, F463L, F463L,
477 14
484 14
407 14
402 14 H402R,
400 14 I400N,
530 15
536 15 A536X,
485 15 H485X,