KCNH2 Variant V503A

Summary of observed carriers, functional annotations, and structural context for KCNH2 V503A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

90% CI: 2.2% – 36.8%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

V503A 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: 119% of WT with a standard error of 8%. 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 (%)
-3.682 0.454 0 0.873 32

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 V503A.
Neighbour residue Distance (Å) Observed variants
503 0
502 4 M502I, M502I, M502I,
504 4 A504V,
506 5 I506V,
505 6 A505V,
500 6 I500Del,
527 6
530 7
501 7 D501N, D501H, D501Y,
499 7
531 8 R531W, R531Del, R531Q,
498 9
528 9 R528W, R528X, R528P,
507 9 P507S, P507L,
526 10
524 10
508 10
529 10
463 10 F463L, F463L, F463L,
534 11 R534C,
467 11
533 11
464 11 I464X,
525 12 K525N, K525N,
460 12 D460fsX,
497 12 W497L, W497X,
496 13
532 13
493 13 Y493H, Y493C, Y493F, Y493Ins,
466 13 D466E, D466E,
421 13 T421fsX, T421M,
494 14 F494Del,
523 14
425 14
459 14
537 14 R537W
418 15
461 15
522 15 G522E,
470 15 N470D,