KCNH2 Variant A478G Detail

We estimate the penetrance of LQTS for KCNH2 A478G is 16%. We are unaware of any observations of this variant in individuals. A478G is not present in gnomAD. A478G 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A478G around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.698 0.153 -1 0.521 16
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 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.

A478G 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
478 0 A478D,
479 4
477 4
480 5 E480V,
476 7 V476I,
481 7
827 8
4 9
475 9 Y475Del, Y475C,
482 9 V482A,
703 9
6 10 G6R,
706 10 S706C, S706F,
483 10 V483I,
492 11 H492Y,
765 11
702 11
826 12 T826A, T826I,
764 12
707 12
699 12 E699D, E699D,
7 13
704 13 A704V, A704T,
5 13
8 13
9 14 A9V, A9T,
488 14 R488H, R488C,
474 14 T474I,
762 14
402 14 H402R,
828 14
763 14
705 14 W705X, W705fsX,
3 14
484 14
489 14 I489I, I489F,
829 15 D829E, D829E, D829A,
709 15
825 15
491 15 V491I,
784 15 R784G, R784Q, R784W,
700 15