KCNH2 Variant L559F Detail

We estimate the penetrance of LQTS for KCNH2 L559F is 74%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 1 had LQTS. L559F is not present in gnomAD. L559F has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L559F around 74% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 0.998 0 0.948 80
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: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

L559F has 55 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
559 0 L559H, L559F,
558 4 A558P, A558V, A558E,
560 5 I560fsX, I560M,
563 5 W563C, W563C, W563X, W563G,
556 5
562 5 H562R, H562P, H562Q, H562Q,
555 6
561 6 A561P, A561V, A561T,
422 6 A422T,
423 7
419 7
557 8
564 9 L564L,
426 10 P426H,
554 10
532 10
421 10 T421M, T421fsX,
552 10 L552S,
565 10
418 10
619 10
566 10 C566F, C566R, C566G, C566S, C566S,
615 10 L615F, L615V,
529 11
553 11 L553V,
424 11
425 11
618 11 T618S, T618S,
551 11 F551L, F551L, F551L,
651 12 M651K,
420 12 Y420C,
611 12 Y611D,
415 12
622 12 L622F,
646 12
567 12 I567M, I567T,
655 13
427 13 Y427C, Y427H, Y427S,
416 13
535 13 V535M,
647 13
642 13 I642Del, I642V,
614 14 A614V, A614T,
417 14
648 14 G648A,
644 14 V644F, V644I,
531 14 R531Del, R531Q, R531W,
550 14
533 14
656 14 F656L, F656L, F656L,
428 15 S428X, S428fsX, S428L,
530 15
526 15
623 15 T623I,
612 15 V612L, V612L, V612A,