KCNH2 Variant G446D Detail

We estimate the penetrance of LQTS for KCNH2 G446D is 32%. We are unaware of any observations of this variant in individuals. G446D is not present in gnomAD. G446D has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G446D around 32% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.63 0.855 -1 0.749 39
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 7 3 -
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.

G446D has 31 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
446 0
445 4
447 4 Y447X,
444 5 E444D, E444K, E444D,
448 5 A448T, A448S,
443 7 T443N, T443fsX,
449 7
442 8
450 8
441 8 P441R, P441L,
451 8 P451L,
440 9 P440L,
452 9
439 10
453 10
438 11 E438K, E438X,
454 11
437 11
455 11
436 12 T436M,
456 12 D456Y,
435 13 E435G, E435X,
457 13 L457P,
434 13
458 13
433 14
459 14
432 14
460 14 D460fsX,
431 15 F431L, F431L, F431L,
461 15