KCNH2 Variant T474I Detail

We estimate the penetrance of LQTS for KCNH2 T474I is 72%. This variant was found in a total of 4 carriers in 2 papers or gnomAD, 3 had LQTS. T474I is not present in gnomAD. T474I has been functionally characterized in 2 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 T474I around 72% (10/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 0.997 -1 0.976 76
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
Japan Cohort 2020 4 1 3
23631430 2013 1 0
LITERATURE, COHORT, AND GNOMAD: - 4 1 3 -
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)
9694858 HEK293 77 58 -27.3 None None None
9721698 Xeno 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)
9694858 HEK293 None None None
9721698 Xeno 32 50 3.1 -2.7 1.0

T474I has 50 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
474 0 T474I,
473 4 T473P,
402 5 H402R,
475 5 Y475Del, Y475C,
401 6
483 6 V483I,
484 6
400 7 I400N,
489 7 I489I, I489F,
482 8 V482A,
476 8 V476I,
403 8
399 9
470 9 N470D,
407 9
472 9 R472C, R472X,
485 9 H485X,
404 10
469 10
481 10
471 10 F471X,
486 10
6 11 G6R,
492 11 H492Y,
477 11
488 11 R488C, R488H,
5 11
480 11 E480V,
493 11 Y493C, Y493H, Y493Ins, Y493F,
490 12 A490T, A490P,
398 12 W398X, W398L,
3 12
4 12
487 12 G487S, G487R,
406 12
8 13
408 13
541 13 R541C, R541H,
538 13
405 13
466 13 D466E, D466E,
411 13
491 13 V491I,
537 13 R537W,
468 14 L468R, L468X, L468F,
478 14 A478D,
410 14 W410X,
7 14
467 14
9 14 A9T, A9V,