KCNH2 Variant Y403F Detail

We estimate the penetrance of LQTS for KCNH2 Y403F is 57%. We are unaware of any observations of this variant in individuals. Y403F is not present in gnomAD. Y403F 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y403F around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.802 0.999 3 0.897 73
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 5 5 -
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.

Y403F has 42 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
403 0
402 5 H402R,
404 5
401 5
5 6
405 8
474 8 T474I,
3 9
6 9 G6R,
407 9
400 10 I400N,
408 10
482 10 V482A,
695 10
541 10 R541C, R541H,
476 11 V476I,
473 11 T473P,
4 11
406 11
8 11
7 11
481 12
698 12 E698K, E698X,
691 12
483 12 V483I,
399 12
475 12 Y475Del, Y475C,
694 12 R694H, R694C,
484 12
699 13 E699D, E699D,
409 13 V409M, V409L, V409L,
411 13
544 13 E544fsX, E544A,
540 14 D540fsX,
692 14
702 14
538 15
480 15 E480V,
9 15 A9T, A9V,
469 15
410 15 W410X,
470 15 N470D,