KCNH2 Variant V476F Detail

We estimate the penetrance of LQTS for KCNH2 V476F is 26%. We are unaware of any observations of this variant in individuals. V476F is not present in gnomAD. V476F 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 V476F around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.567 1.0 -1 0.894 31
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.

V476F has 48 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
476 0 V476I,
475 5 Y475C, Y475Del,
477 5
481 6
4 6
482 6 V482A,
480 7 E480V,
478 7 A478D,
6 7 G6R,
483 7 V483I,
402 7 H402R,
474 8 T474I,
5 9
479 9
3 9
492 10 H492Y,
484 11
403 11
489 11 I489F, I489I,
473 11 T473P,
702 11
7 11
401 12
8 12
699 12 E699D, E699D,
488 12 R488C, R488H,
540 12 D540fsX,
703 12
827 12
537 13 R537W,
541 13 R541C, R541H,
538 13
706 13 S706F, S706C,
9 13 A9T, A9V,
470 13 N470D,
765 13
493 13 Y493Ins, Y493H, Y493F, Y493C,
407 14
698 14 E698K, E698X,
404 14
491 14 V491I,
400 14 I400N,
497 14 W497X, W497L,
490 14 A490T, A490P,
695 14
485 14 H485X,
496 15
764 15