KCNH2 Variant A504S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A504S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A504S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 105% 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 (%)
-2.813 0.759 1 0.847 49

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 A504S.
Neighbour residue Distance (Å) Observed variants
504 0 A504V,
505 4 A505V,
503 4
531 5 R531W, R531Del, R531Q,
502 5 M502I, M502I, M502I,
506 6 I506V,
527 6
501 6 D501N, D501H, D501Y,
530 6
528 6 R528W, R528X, R528P,
463 7 F463L, F463L, F463L,
500 8 I500Del,
507 8 P507S, P507L,
460 8 D460fsX,
464 9 I464X,
534 9 R534C,
529 9
467 9
498 10
499 10
526 10
421 10 T421fsX, T421M,
533 10
466 10 D466E, D466E,
459 10
525 10 K525N, K525N,
508 10
532 11
524 11
418 11
461 11
462 12 M462Ins,
425 12
465 12
417 12
456 12 D456Y,
497 13 W497L, W497X,
414 13 I414fsX,
457 13 L457P,
422 13 A422T,
493 13 Y493H, Y493C, Y493F, Y493Ins,
470 13 N470D,
537 13 R537W
468 13 L468F, L468X, L468R,
420 13 Y420C,
535 14 V535M,
496 14
458 14
523 15
522 15 G522E,
469 15