KCNH2 Variant V483F Detail

We estimate the penetrance of LQTS for KCNH2 V483F is 28%. We are unaware of any observations of this variant in individuals. V483F is not present in gnomAD. V483F 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V483F around 28% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.633 0.998 -1 0.905 34
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 8 2 -
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.

V483F has 43 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
483 0 V483I,
484 4
482 4 V482A,
475 5 Y475C, Y475Del,
474 6 T474I,
488 6 R488H, R488C,
480 7 E480V,
489 7 I489F, I489I,
481 7
476 7 V476I,
477 7
485 8 H485X,
473 9 T473P,
402 9 H402R,
492 10 H492Y,
6 10 G6R,
487 10 G487S, G487R,
486 10
8 10
401 10
9 10 A9T, A9V,
478 10 A478D,
479 11
490 11 A490P, A490T,
491 11 V491I,
400 11 I400N,
399 12
403 12
472 12 R472X, R472C,
7 12
5 12
4 12
471 13 F471X,
470 13 N470D,
493 13 Y493C, Y493F, Y493Ins, Y493H,
10 14
13 14 T13N,
398 14 W398L, W398X,
765 14
827 15
404 15
3 15
469 15