KCNH2 Variant A9V Detail

We estimate the penetrance of LQTS for KCNH2 A9V is 4%. This variant was found in a total of 13 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. A9V is present in 13 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 112% of WT with a standard error of 15%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. A9V has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A9V around 4% (0/23).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.186 0.943 -1 0.719 4
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: - 13 5 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

A9V has 44 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
9 0 A9T, A9V,
10 3
8 4
13 6 T13N,
7 6
11 7 Q11H, Q11H, Q11L,
482 7 V482A,
765 8
481 8
825 8
12 9 N12D,
766 9
480 9 E480V,
6 9 G6R,
826 10 T826I, T826A,
14 10
483 10 V483I,
824 10
16 11 D16A,
484 11
827 12
764 12
17 12
823 12 R823W, R823fsX, R823T, R823Q,
15 12 L15V,
767 12 D767X,
479 12
699 13 E699D, E699D,
5 13
788 13 E788K, E788D, E788D,
477 13
786 13
695 13
476 13 V476I,
488 13 R488C, R488H,
478 14 A478D,
485 14 H485X,
696 14 R696C, R696H,
828 14
763 14
475 14 Y475Del, Y475C,
474 14 T474I,
403 15
787 15