KCNH2 Variant Y493F Detail

We estimate the penetrance of LQTS for KCNH2 Y493F is 81%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. Y493F is not present in gnomAD. Y493F 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y493F around 81% (9/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 1.0 3 0.948 95
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
19668779 2009 2 0 2 Seizures
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
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)
19668779 Xeno 54 -11.6 1.0 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)
19668779 Xeno 50 -1.9 5.1 None

Y493F has 47 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
493 0 Y493H, Y493C, Y493Ins, Y493F,
498 5
494 6 F494Del,
471 6 F471X,
470 6 N470D,
490 6 A490P, A490T,
492 6 H492Y,
496 7
489 7 I489I, I489F,
467 7
497 8 W497L, W497X,
501 8 D501Y, D501H, D501N,
491 8 V491I,
499 9
473 9 T473P,
495 9 K495X,
537 10 R537W,
475 10 Y475Del, Y475C,
502 10 M502I, M502I, M502I,
466 10 D466E, D466E,
469 10
468 10 L468R, L468X, L468F,
500 10 I500Del,
534 11 R534C,
474 11 T474I,
472 11 R472X, R472C,
486 12
487 12 G487R, G487S,
538 12
533 13
483 13 V483I,
465 13
503 13
464 13 I464X,
505 13 A505V,
504 13 A504V,
488 13 R488H, R488C,
476 13 V476I,
463 14 F463L, F463L, F463L,
477 14
484 14
407 14
402 14 H402R,
400 14 I400N,
530 15
536 15 A536X,
485 15 H485X,