KCNH2 Variant S354T Detail

We estimate the penetrance of LQTS for KCNH2 S354T is 7%. We are unaware of any observations of this variant in individuals. S354T is not present in gnomAD. S354T has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S354T around 7% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.149 0.112 1 0.401 1
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
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.

S354T has 31 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
354 0
353 4 T353S, T353S,
355 4 D355G,
352 5
356 5 R356C, R356H,
351 7 S351L,
357 7 E357D, E357D,
350 8
358 8
349 8
359 8 I359V,
348 9
360 9
347 10 P347S,
361 10
346 11 D346E, D346N, D346E, D346Y,
362 11
345 11 G345S,
363 11 I363X,
344 12
364 12 K364X,
343 13 L343fsX,
365 13 E365G,
342 13 D342V, D342X, D342A,
366 13 R366Q, R366X,
341 14
367 14 T367S, T367S,
340 14 F340L, F340L, F340L,
368 14 H368Y,
339 15
369 15 N369K, N369K,