KCNH2 Variant F640L Detail

We estimate the penetrance of LQTS for KCNH2 F640L is 84%. This variant was found in a total of 2 carriers in 2 papers or gnomAD, 2 had LQTS. F640L is not present in gnomAD. F640L 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F640L around 84% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.801 0.93 0 0.914 91
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
19038855 2009 1 0 1 Seizure
10220144 1999 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 2 8 -
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.

F640L has 64 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
640 0 F640Del, F640L, F640L, F640L, F640V,
641 5 S641F, S641P,
643 5
644 6 V644I, V644F,
568 6 W568C, W568C,
639 6 I639F, I639N,
564 7 L564L,
567 7 I567T, I567M,
637 7 E637X, E637K, E637G,
642 7 I642V, I642Del,
636 7
571 8 I571L, I571V,
617 8 F617L, F617V, F617L, F617L,
618 8 T618S, T618S,
638 8 K638E, K638R, K638D, K638Del,
645 9 M645I, M645V, M645L, M645L, M645R, M645I, M645I,
632 9 P632S, P632A,
621 9 S621R, S621N, S621R, S621R,
565 9
647 10
570 10
634 10 T634S, T634S, T634I, T634A, T634P,
616 10 Y616S,
646 11
614 11 A614T, A614V,
622 11 L622F,
566 11 C566S, C566R, C566G, C566F, C566S,
585 11 W585C, W585C,
561 11 A561P, A561V, A561T,
635 11 N635I,
631 11 S631F,
572 11 G572C, G572R, G572S, G572D,
627 11 F627X, F627L, F627L, F627fsX, F627L,
648 12 G648A,
620 12 S620G, S620I,
630 12 V630A, V630T, V630I,
569 12 Y569X, Y569H, Y569C,
612 12 V612L, V612L, V612A,
560 12 I560M, I560fsX,
633 12 N633D, N633I, N633S,
619 12
563 13 W563C, W563X, W563C, W563G,
615 13 L615F, L615V,
575 13 E575K,
615 13 L615F, L615V,
619 13
620 13 S620G, S620I,
625 13 V625E,
562 14 H562Q, H562R, H562Q, H562P,
613 14 T613A, T613K, T613M, T613L,
584 14 G584S, G584C, G584R,
574 14 M574L, M574L, M574V,
649 14
613 14 T613A, T613K, T613M, T613L,
573 14
629 14 N629S, N629I, N629K, N629D, N629K, N629T,
616 14 Y616S,
623 14 T623I,
626 14 G626V, G626A, G626S,
623 14 T623I,
586 14 L586M,
624 15 S624R, S624N, S624R, S624R,
626 15 G626V, G626A, G626S,
651 15 M651K,