KCNH2 Variant R528P

Summary of observed carriers, functional annotations, and structural context for KCNH2 R528P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

R528P 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: 24% of WT with a standard error of 21%. 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 (%)
-6.709 0.741 -2 0.96 39

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
16922724 2006 1 1
Literature, cohort, and gnomAD – 1 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 R528P.
Neighbour residue Distance (Å) Observed variants
528 0 R528X, R528P, R528W,
527 5
525 5 K525N, K525N
531 6 R531Q, R531Del, R531W,
425 6
421 6 T421M, T421fsX,
504 6 A504V,
526 6
529 7
460 7 D460fsX,
456 8 D456Y,
530 8
459 8
505 9 A505V,
507 9 P507S, P507L,
524 9
463 9 F463L, F463L, F463L,
506 9 I506V,
420 9 Y420C,
422 9 A422T,
503 9
426 9 P426H,
428 10 S428X, S428fsX, S428L,
418 10
508 10
424 10
522 10 G522E,
457 11 L457P,
429 11 A429V, A429P,
417 11
523 11
423 11
532 11
502 12 M502I, M502I, M502I,
501 12 D501N, D501Y, D501H,
461 12
464 12 I464X,
534 12 R534C,
453 12
458 12
419 12
455 12
500 13 I500Del,
462 13 M462Ins,
533 13
452 13
563 13 W563X, W563G, W563C, W563C,
427 13 Y427C, Y427S, Y427H,
521 14
414 14 I414fsX,
430 14
454 14
509 14 D509N,
466 14 D466E, D466E,
432 15
467 15
416 15
562 15 H562P, H562Q, H562R, H562Q,