KCNH2 Variant R541C Detail

We estimate the penetrance of LQTS for KCNH2 R541C is 10%. This variant was found in a total of 3 carriers in 0 papers or gnomAD, 0 had LQTS. R541C is present in 3 alleles in gnomAD. R541C has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R541C around 10% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.668 1.0 -3 0.955 6
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 3 3 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

R541C has 54 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
541 0 R541C, R541H,
540 5 D540fsX,
3 5
542 5
408 6
411 6
538 7
544 7 E544fsX, E544A,
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 H674fsX, H674Y,
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,