KCNH2 Variant V482A Detail

We estimate the penetrance of LQTS for KCNH2 V482A is 38%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 1 had LQTS. V482A is not present in gnomAD. V482A 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V482A around 38% (4/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 0.993 0 0.948 46
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
Italy Cohort 2020 2 1 1
LITERATURE, COHORT, AND GNOMAD: - 2 1 1 -
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.

V482A has 45 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
482 0 V482A,
481 4
483 4 V483I,
480 5 E480V,
6 6 G6R,
8 6
476 6 V476I,
484 7
475 7 Y475C, Y475Del,
9 7 A9T, A9V,
477 8
474 8 T474I,
7 8
402 9 H402R,
5 9
478 9 A478D,
488 10 R488C, R488H,
479 10
403 10
401 10
4 10
10 11
485 11 H485X,
765 11
489 11 I489F, I489I,
699 12 E699D, E699D,
473 12 T473P,
827 12
13 12 T13N,
492 13 H492Y,
695 13
400 13 I400N,
3 13
399 13
766 13
826 13 T826I, T826A,
764 14
487 14 G487S, G487R,
486 14
825 14
404 14
11 14 Q11H, Q11L, Q11H,
702 14
703 14
698 15 E698X, E698K,