KCNH2 Variant S404T Detail

We estimate the penetrance of LQTS for KCNH2 S404T is 40%. We are unaware of any observations of this variant in individuals. S404T is not present in gnomAD. S404T 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S404T around 40% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.855 0.998 1 0.93 52
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 6 4 -
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.

S404T 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
404 0
405 4
403 5
401 5
407 6
406 6
408 6
402 7 H402R,
400 8 I400N,
409 9 V409L, V409L, V409M,
474 10 T474I,
541 10 R541H, R541C,
473 10 T473P,
411 10
5 10
410 11 W410X,
3 11
399 11
469 12
412 13 W412X,
470 13 N470D,
6 14 G6R,
538 14
544 14 E544A, E544fsX,
476 14 V476I,
482 14 V482A,
398 14 W398L, W398X,
475 14 Y475C, Y475Del,
413 14 L413P,
472 14 R472X, R472C,
484 14
542 14
695 15
540 15 D540fsX,
466 15 D466E, D466E,
414 15 I414fsX,
4 15
483 15 V483I,
691 15