KCNH2 Variant I400F Detail

We estimate the penetrance of LQTS for KCNH2 I400F is 71%. We are unaware of any observations of this variant in individuals. I400F is not present in gnomAD. I400F has not been functionally characterized. 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 I400F around 71% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.685 0.996 0 0.9 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
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.

I400F 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 R472C, R472X,
398 7 W398L, W398X,
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 I489I, I489F,
468 11 L468R, L468F, L468X,
483 11 V483I,
486 11
410 12 W410X,
475 12 Y475C, Y475Del,
408 12
466 12 D466E, D466E,
482 13 V482A,
465 13
411 13
409 14 V409L, V409M, V409L,
467 14
476 14 V476I,
493 14 Y493Ins, Y493H, Y493C, Y493F,
5 14
490 15 A490T, A490P,
541 15 R541H, R541C,
487 15 G487R, G487S,
488 15 R488H, R488C,