KCNH2 Variant F619L Detail

We estimate the penetrance of LQTS for KCNH2 F619L is 68%. We are unaware of any observations of this variant in individuals. F619L is not present in gnomAD. F619L 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F619L around 68% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.607 0.091 0 0.835 75
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 4 6 -
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.

F619L has 79 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
619 0
618 5 T618S, T618S,
645 5 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
615 6 L615V, L615F,
642 6 I642Del, I642V,
622 6 L622F,
561 6 A561V, A561P, A561T,
620 6 S620I, S620G,
623 6 T623I,
557 7
646 7
558 7 A558V, A558P, A558E,
621 7 S621N, S621R, S621R, S621R,
616 8 Y616S,
617 8 F617V, F617L, F617L, F617L,
641 8 S641F, S641P,
560 9 I560fsX, I560M,
614 9 A614T, A614V,
564 9 L564L,
565 9
625 9 V625E,
649 9
643 9
562 10 H562Q, H562Q, H562R, H562P,
644 10 V644F, V644I,
624 10 S624R, S624R, S624R, S624N,
644 10 V644F, V644I,
612 10 V612L, V612A, V612L,
559 10 L559F, L559H,
639 11 I639F, I639N,
652 11 Y652X,
648 11 G648A,
627 11 F627X, F627L, F627fsX, F627L, F627L,
648 11 G648A,
613 11 T613A, T613L, T613K, T613M,
554 11
638 11 K638Del, K638E, K638D, K638R,
626 11 G626A, G626S, G626V,
611 11 Y611D,
621 11 S621N, S621R, S621R, S621R,
647 11
556 12
651 12 M651K,
563 12 W563X, W563C, W563G, W563C,
624 12 S624R, S624R, S624R, S624N,
656 12 F656L, F656L, F656L,
568 12 W568C, W568C,
640 12 F640L, F640V, F640L, F640L, F640Del,
555 12
647 12
566 12 C566G, C566S, C566R, C566F, C566S,
630 12 V630I, V630T, V630A,
625 13 V625E,
650 13 L650X,
645 13 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
640 13 F640L, F640V, F640L, F640L, F640Del,
632 13 P632S, P632A,
641 13 S641F, S641P,
655 13
622 13 L622F,
567 14 I567M, I567T,
627 14 F627X, F627L, F627fsX, F627L, F627L,
649 14
626 14 G626A, G626S, G626V,
629 14 N629K, N629S, N629K, N629I, N629D, N629T,
628 14 G628V, G628R, G628A, G628D, G628Del, G628S,
423 14
643 14
553 14 L553V,
624 15 S624R, S624R, S624R, S624N,
620 15 S620I, S620G,
625 15 V625E,
626 15 G626A, G626S, G626V,
623 15 T623I,
635 15 N635I,
609 15 D609N, D609G,
623 15 T623I,
631 15 S631F,
637 15 E637G, E637X, E637K,