KCNH2 Variant I400N Detail

We estimate the penetrance of LQTS for KCNH2 I400N is 82%. This variant was found in a total of 8 carriers in 2 papers or gnomAD, 7 had LQTS. I400N is not present in gnomAD. I400N 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 I400N around 82% (14/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.424 1.0 -3 0.931 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
24606995 2014 1 0 1
24021552 2013 10 1 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)
24021552 HEK293 20 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)
24021552 HEK293 None None None

I400N has 38 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
400 0 I400N,
401 4
399 4
473 5 T473P,
474 7 T474I,
472 7 R472X, R472C,
398 7 W398X, W398L,
469 8
404 8
406 8
407 8
402 9 H402R,
403 10
484 10
470 10 N470D,
485 10 H485X,
405 10
471 11 F471X,
489 11 I489F, I489I,
468 11 L468X, L468F, L468R,
483 11 V483I,
486 11
410 12 W410X,
475 12 Y475Del, Y475C,
408 12
466 12 D466E, D466E,
482 13 V482A,
465 13
411 13
409 14 V409M, V409L, V409L,
467 14
476 14 V476I,
493 14 Y493F, Y493H, Y493C, Y493Ins,
5 14
490 15 A490P, A490T,
541 15 R541C, R541H,
487 15 G487S, G487R,
488 15 R488H, R488C,