KCNH2 Variant A505V

Summary of observed carriers, functional annotations, and structural context for KCNH2 A505V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

90% CI: 1.0% – 29.1%

1/10 effective observations

Total carriers

0

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

A505V 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: 101% of WT with a standard error of 9%. 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 (%)
-3.773 0.984 0 0.886 26

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 1 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 A505V.
Neighbour residue Distance (Å) Observed variants
505 0 A505V,
504 4 A504V,
506 4 I506V,
502 5 M502I, M502I, M502I,
503 6
464 6 I464X,
507 6 P507S, P507L,
463 7 F463L, F463L, F463L,
460 7 D460fsX,
501 8 D501N, D501H, D501Y,
531 8 R531W, R531Del, R531Q,
467 8
528 9 R528W, R528X, R528P,
527 9
461 9
508 9
498 10
530 10
466 10 D466E, D466E,
500 10 I500Del,
465 10
459 10
534 11 R534C
462 11 M462Ins,
499 11
468 11 L468F, L468X, L468R,
457 12 L457P,
525 12 K525N, K525N,
524 12
456 12 D456Y,
529 13
421 13 T421fsX, T421M,
526 13
470 13 N470D,
493 13 Y493H, Y493C, Y493F, Y493Ins,
458 13
533 13
417 13
418 14
471 14 F471X,
469 14
414 14 I414fsX,
532 14
425 14
509 14 D509N,
497 15 W497L, W497X,
494 15 F494Del,