KCNH2 Variant F627L Detail

We estimate the penetrance of LQTS for KCNH2 F627L is 87%. This variant was found in a total of 3 carriers in 4 papers or gnomAD, 3 had LQTS. F627L is not present in gnomAD. F627L has been functionally characterized in 1 papers. 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 F627L around 87% (11/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.801 0.999 0 0.933 94
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
18848812 2008 2 0 2
11854117 2002 1 0 1
10973849 2000 1 0 1
24217263 2013 1 0 congenital LQT
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
18848812 None 0 None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
18848812 None 25 None None None

F627L has 91 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
627 0 F627X, F627L, F627L, F627fsX, F627L,
626 4 G626S, G626V, G626A,
626 5 G626S, G626V, G626A,
625 5 V625E,
628 6 G628R, G628D, G628V, G628A, G628S, G628Del,
620 6 S620I, S620G,
629 6 N629T, N629I, N629S, N629D, N629K, N629K,
616 6 Y616S,
631 6 S631F,
632 7 P632A, P632S,
628 7 G628R, G628D, G628V, G628A, G628S, G628Del,
621 7 S621R, S621R, S621N, S621R,
641 7 S641P, S641F,
630 8 V630A, V630I, V630T,
630 8 V630A, V630I, V630T,
620 8 S620I, S620G,
617 8 F617V, F617L, F617L, F617L,
645 8 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
625 8 V625E,
627 9 F627X, F627L, F627L, F627fsX, F627L,
627 9 F627X, F627L, F627L, F627fsX, F627L,
626 9 G626S, G626V, G626A,
617 9 F617V, F617L, F617L, F617L,
638 9 K638R, K638Del, K638D, K638E,
624 9 S624R, S624R, S624N, S624R,
625 9 V625E,
626 9 G626S, G626V, G626A,
621 9 S621R, S621R, S621N, S621R,
624 9 S624R, S624R, S624N, S624R,
623 10 T623I,
631 10 S631F,
642 10 I642V, I642Del,
629 10 N629T, N629I, N629S, N629D, N629K, N629K,
633 10 N633I, N633D, N633S,
628 10 G628R, G628D, G628V, G628A, G628S, G628Del,
644 11 V644F, V644I,
619 11
637 11 E637K, E637G, E637X,
613 11 T613A, T613K, T613M, T613L,
628 11 G628R, G628D, G628V, G628A, G628S, G628Del,
625 11 V625E,
618 11 T618S, T618S,
618 11 T618S, T618S,
616 11 Y616S,
640 11 F640L, F640Del, F640L, F640V, F640L,
623 12 T623I,
622 12 L622F,
624 12 S624R, S624R, S624N, S624R,
568 12 W568C, W568C,
627 12 F627X, F627L, F627L, F627fsX, F627L,
624 12 S624R, S624R, S624N, S624R,
622 12 L622F,
615 12 L615V, L615F,
629 12 N629T, N629I, N629S, N629D, N629K, N629K,
614 12 A614V, A614T,
632 13 P632A, P632S,
639 13 I639N, I639F,
634 13 T634P, T634I, T634S, T634A, T634S,
585 13 W585C, W585C,
592 13 Q592X,
612 13 V612L, V612A, V612L,
643 13
620 13 S620I, S620G,
631 13 S631F,
648 14 G648A,
619 14
614 14 A614V, A614T,
645 14 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
588 14 N588K, N588K, N588D,
641 14 S641P, S641F,
613 14 T613A, T613K, T613M, T613L,
646 14
632 14 P632A, P632S,
636 14
621 14 S621R, S621R, S621N, S621R,
645 14 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
620 14 S620I, S620G,
584 14 G584C, G584R, G584S,
635 14 N635I,
649 14
589 14 L589P,
568 14 W568C, W568C,
585 14 W585C, W585C,
588 14 N588K, N588K, N588D,
629 15 N629T, N629I, N629S, N629D, N629K, N629K,
623 15 T623I,
644 15 V644F, V644I,
630 15 V630A, V630I, V630T,
616 15 Y616S,
564 15 L564L,
630 15 V630A, V630I, V630T,