KCNH2 Variant T473P Detail

We estimate the penetrance of LQTS for KCNH2 T473P is 84%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. T473P is not present in gnomAD. T473P 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 T473P around 84% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 1.0 -1 0.978 87
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
23010577 2013 2 0 2
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.

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)
23010577 CHO 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)
23010577 CHO 13 1.4 -3.0 None

T473P has 55 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
473 0 T473P,
474 4 T474I,
400 5 I400N,
470 5 N470D,
469 6
472 6 R472C, R472X,
401 7
471 7 F471X,
489 7 I489F, I489I,
402 7 H402R,
407 8
475 8 Y475C, Y475Del,
399 8
484 9
483 9 V483I,
493 9 Y493Ins, Y493F, Y493H, Y493C,
468 9 L468F, L468X, L468R,
466 10 D466E, D466E,
486 10
404 10
485 10 H485X,
398 10 W398X, W398L,
467 10
406 10
490 10 A490P, A490T,
403 11
476 11 V476I,
492 11 H492Y,
410 11 W410X,
482 12 V482A,
411 12
465 12
487 12 G487R, G487S,
538 12
408 12
488 12 R488C, R488H,
537 13 R537W,
405 13
491 13 V491I,
541 13 R541H, R541C,
534 13 R534C,
498 13
477 14
494 14 F494Del,
3 14
501 14 D501H, D501N, D501Y,
481 14
497 14 W497X, W497L,
414 14 I414fsX,
5 14
6 15 G6R,
409 15 V409L, V409L, V409M,
480 15 E480V,
464 15 I464X,
496 15