KCNH2 Variant E357V Detail

We estimate the penetrance of LQTS for KCNH2 E357V is 10%. We are unaware of any observations of this variant in individuals. E357V is not present in gnomAD. E357V 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 E357V around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.578 0.23 -2 0.717 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.

E357V 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
357 0 E357D, E357D,
356 4 R356H, R356C,
358 4
355 5 D355G,
359 5 I359V,
354 7
360 7
353 8 T353S, T353S,
361 8
352 8
362 8
351 9 S351L,
363 9 I363X,
350 10
364 10 K364X,
349 11
365 11 E365G,
348 11
366 11 R366X, R366Q,
347 12 P347S,
367 12 T367S, T367S,
346 13 D346E, D346Y, D346E, D346N,
368 13 H368Y,
345 13 G345S,
369 13 N369K, N369K,
344 14
370 14
343 14 L343fsX,
371 14
342 15 D342V, D342X, D342A,
372 15