KCNH2 Variant R541C

Summary of observed carriers, functional annotations, and structural context for KCNH2 R541C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

1/15 effective observations

Total carriers

5

0 LQT2 · 3 unaffected

Functional studies

0

Publications with functional data

R541C is present in 5 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 87% 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 (%)
-7.668 1.0 -3 0.955 6

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 – 5 3 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 R541C.
Neighbour residue Distance (Å) Observed variants
541 0 R541C, R541H,
540 5 D540fsX,
3 5
542 5
408 6
411 6
538 7
544 7 E544A, E544fsX,
412 7 W412X,
407 8
543 8 S543fsX,
539 8
402 9 H402R,
409 9 V409M, V409L, V409L,
545 9
404 10
535 10 V535M,
405 10
403 10
537 11 R537W,
415 11
414 11 I414fsX,
410 11 W410X,
4 11
536 11 A536X,
548 12
5 12
406 12
413 12 L413P,
401 13
534 13 R534C,
549 13 V549M,
476 13 V476I,
474 13 T474I,
552 13 L552S,
473 13 T473P,
681 13 R681W,
546 13
674 14 H674Y, H674fsX,
470 14 N470D,
702 14
698 14 E698K, E698X
466 14 D466E, D466E,
677 14 M677T,
673 14
547 14 A547T,
475 15 Y475C, Y475Del,
469 15
416 15
6 15 G6R,
400 15 I400N,
533 15
418 15
551 15 F551L, F551L, F551L,