KCNH2 Variant V491D Detail

We estimate the penetrance of LQTS for KCNH2 V491D is 35%. We are unaware of any observations of this variant in individuals. V491D is not present in gnomAD. V491D 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 V491D around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.531 0.983 -3 0.903 37
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
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.

V491D has 28 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
491 0 V491I,
490 4 A490P, A490T,
492 6 H492Y,
494 6 F494Del,
489 6 I489I, I489F,
487 7 G487R, G487S,
488 8 R488H, R488C,
493 8 Y493F, Y493C, Y493H, Y493Ins,
495 8 K495X,
486 10
475 10 Y475C, Y475Del,
496 10
471 10 F471X,
498 11
483 11 V483I,
477 12
484 12
485 13 H485X,
470 13 N470D,
473 13 T473P,
497 13 W497X, W497L,
474 13 T474I,
472 14 R472X, R472C,
499 14
480 14 E480V,
476 14 V476I,
467 15
478 15 A478D,