KCNH2 Variant R537P

Summary of observed carriers, functional annotations, and structural context for KCNH2 R537P. 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

R537P has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 74% of WT with a standard error of 14%. 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 1.0 -2 0.954 59

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 R537P.
Neighbour residue Distance (Å) Observed variants
537 0 R537W,
538 4
497 5 W497L, W497X,
536 5 A536X,
534 6 R534C,
533 6
535 7 V535M,
501 8 D501N, D501H, D501Y,
539 9
496 9
470 9 N470D,
493 10 Y493H, Y493C, Y493F, Y493Ins,
500 10 I500Del,
532 10
540 10 D540fsX,
411 10
542 10
466 11 D466E, D466E,
541 11 R541C, R541H,
414 11 I414fsX,
498 11
492 11 H492Y,
530 11
407 12
467 12
475 12 Y475C, Y475Del,
415 12
531 12 R531W, R531Del, R531Q,
499 12
418 12
3 13
473 13 T473P,
476 13 V476I,
463 13 F463L, F463L, F463L,
402 13 H402R,
469 13
502 13 M502I, M502I, M502I,
410 13 W410X,
474 13 T474I,
504 13 A504V,
543 14 S543fsX
471 14 F471X,
408 14
412 14 W412X,
4 14
495 14 K495X,
494 14 F494Del,
489 14 I489F, I489I,
503 14
417 15
529 15
477 15