KCNH2 Variant A490T Detail

We estimate the penetrance of LQTS for KCNH2 A490T is 27%. This variant was found in a total of 12 carriers in 5 papers or gnomAD (version 4), 7 had LQTS. A490T is not present in gnomAD. We have tested the trafficking efficiency of this variant, 51% of WT with a standard error of 15%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. A490T 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A490T around 27% (8/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.697 0.997 0 0.972 71
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
18808722 2008 7 5 2
Japan Cohort 2020 1 0 1
Italy Cohort 2020 3 0 3
11170080 2001 1 0 1
20975234 2010 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 12 5 7 -
VARIANT FEATURES ALONE: - 10 9 1 -
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)
11170080 HEK293 61 6.0 None None None
20975234 CHO 10 None 14.1 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)
11170080 HEK293 None None None
20975234 CHO 24 None 25.8 1.0

A490T has 32 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
490 0 A490T, A490P,
491 4 V491I,
489 4 I489F, I489I,
494 5 F494Del,
487 6 G487S, G487R,
493 6 Y493Ins, Y493F, Y493H, Y493C,
471 6 F471X,
492 7 H492Y,
486 7
488 9 R488H, R488C,
498 9
475 10 Y475Del, Y475C,
470 10 N470D,
472 10 R472X, R472C,
495 10 K495X,
473 10 T473P,
496 11
485 11 H485X,
483 11 V483I,
484 11
467 12
474 12 T474I,
468 12 L468X, L468F, L468R,
469 13
497 13 W497X, W497L,
477 13
499 13
501 14 D501Y, D501H, D501N,
476 14 V476I,
502 14 M502I, M502I, M502I,
466 15 D466E, D466E,
400 15 I400N,