KCNH2 Variant L553F Detail

We estimate the penetrance of LQTS for KCNH2 L553F is 17%. We are unaware of any observations of this variant in individuals. L553F is not present in gnomAD. We have tested the trafficking efficiency of this variant, 113% of WT with a standard error of 27%; 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. L553F 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L553F around 17% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.831 0.999 0 0.931 43
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: - 0 0 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.

L553F has 62 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
553 0 L553V,
552 5 L552S,
655 5
554 6
550 6
556 6
549 6 V549M,
555 7
659 7
658 7
551 7 F551L, F551L, F551L,
656 8 F656L, F656L, F656L,
557 8
548 9
662 9
654 9
651 9 M651K,
657 9 G657S, G657V,
547 10 A547T,
558 10 A558P, A558E, A558V,
546 11
660 11 S660L,
560 11 I560M, I560fsX,
650 11 L650X,
559 11 L559H, L559F,
543 11 S543fsX,
661 11 A661V,
539 11
653 12
663 12
652 12 Y652X,
649 12
542 12
646 12
535 13 V535M,
665 13 R665Q,
415 13
653 13
419 13
536 13 A536X,
650 14 L650X,
561 14 A561P, A561V, A561T,
663 14
532 14
654 14
666 14
648 14 G648A,
622 14 L622F,
667 14 Y667X,
664 14 Q664X,
674 14 H674Y, H674fsX,
545 14
660 14 S660L,
619 14
540 15 D540fsX,
412 15 W412X,
647 15
563 15 W563C, W563C, W563X, W563G,
648 15 G648A,
647 15
670 15
671 15 A671Del, A671G,