KCNH2 Variant S484T Detail

We estimate the penetrance of LQTS for KCNH2 S484T is 25%. We are unaware of any observations of this variant in individuals. S484T is not present in gnomAD. S484T 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 S484T around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.255 0.384 1 0.6 35
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.

S484T has 39 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
484 0
483 4 V483I,
485 4 H485X,
488 6 R488C, R488H,
474 6 T474I,
482 7 V482A,
489 7 I489F, I489I,
486 7
475 8 Y475C, Y475Del,
487 8 G487R, G487S,
399 8
473 9 T473P,
401 9
472 10 R472C, R472X,
400 10 I400N,
480 10 E480V,
481 10
476 11 V476I,
402 11 H402R,
398 11 W398L, W398X,
477 11
490 11 A490P, A490T,
8 11
9 11 A9V, A9T,
492 12 H492Y,
471 12 F471X,
6 12 G6R,
491 12 V491I,
403 12
470 13 N470D,
7 14
493 14 Y493C, Y493H, Y493F, Y493Ins,
469 14
5 14
478 14 A478D,
479 14
404 14
10 15
13 15 T13N,