KCNH2 Variant F463L Detail

We estimate the penetrance of LQTS for KCNH2 F463L is 78%. This variant was found in a total of 8 carriers in 3 papers or gnomAD, 7 had LQTS. F463L is not present in gnomAD. F463L has been functionally characterized in 3 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F463L around 78% (14/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 0.975 0 0.974 79
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
19065538 2008 1 0 1
France Cohort 2020 5 0 5
19215240 2009 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 8 1 7 -
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.

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)
19215240 HEK293 0 None None None None
23980197 Xeno 6.4 None None None
29573040 HEK293 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)
19215240 HEK293 37 50 12.6 None None
23980197 Xeno None None None
29573040 HEK293 29 7.44 -45.32 None

F463L has 59 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
463 0 F463L, F463L, F463L,
531 5 R531Q, R531Del, R531W,
462 6 M462Ins,
466 6 D466E, D466E,
459 6
464 6 I464X,
460 6 D460fsX,
504 7 A504V,
534 7 R534C,
417 7
505 7 A505V,
465 7
414 7 I414fsX,
461 7
467 8
501 8 D501N, D501H, D501Y,
418 8
528 9 R528X, R528W, R528P,
421 9 T421M, T421fsX,
410 10 W410X,
502 10 M502I, M502I, M502I,
458 10
413 10 L413P,
530 10
503 10
456 11 D456Y,
469 11
468 11 L468R, L468X, L468F,
506 11 I506V,
420 11 Y420C,
470 11 N470D,
532 11
457 11 L457P,
533 11
527 11
507 11 P507L, P507S,
415 11
411 12
416 12
529 12
500 12 I500Del,
535 12 V535M,
498 12
419 12
538 12
537 13 R537W,
422 13 A422T,
455 13
425 13
407 13
493 14 Y493H, Y493C, Y493Ins, Y493F,
525 14 K525N, K525N,
471 14 F471X,
497 14 W497L, W497X,
526 14
499 14
424 15
536 15 A536X,
508 15