KCNH2 Variant N477S Detail

We estimate the penetrance of LQTS for KCNH2 N477S is 39%. We are unaware of any observations of this variant in individuals. N477S is not present in gnomAD. N477S 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 N477S around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.6 0.41 0 0.64 48
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 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.

N477S has 40 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
477 0
478 4 A478D,
480 4 E480V,
476 5 V476I,
479 5
475 6 Y475Del, Y475C,
481 6
483 7 V483I,
482 8 V482A,
492 8 H492Y,
4 9
6 10 G6R,
488 10 R488C, R488H,
827 10
474 11 T474I,
489 11 I489I, I489F,
484 11
491 12 V491I,
402 12 H402R,
703 13
8 13
765 13
9 13 A9T, A9V,
7 13
5 13
706 13 S706C, S706F,
490 13 A490P, A490T,
826 13 T826A, T826I,
702 14
473 14 T473P,
487 14 G487R, G487S,
493 14 Y493F, Y493H, Y493C, Y493Ins,
699 14 E699D, E699D,
3 14
496 14
764 14
485 15 H485X,
497 15 W497L, W497X,
537 15 R537W,
495 15 K495X,