KCNH2 Variant E365G Detail

We estimate the penetrance of LQTS for KCNH2 E365G is 60%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. E365G is not present in gnomAD. E365G 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E365G around 60% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.942 0.76 -2 0.82 59
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
23098067 2012 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 5 5 -
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.

E365G 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
365 0 E365G,
364 4 K364X,
366 4 R366X, R366Q,
363 5 I363X,
367 5 T367S, T367S,
362 7
368 7 H368Y,
361 8
369 8 N369K, N369K,
360 8
370 8
359 9 I359V,
371 9
358 10
372 10
357 11 E357D, E357D,
373 11
356 11 R356H, R356C,
374 11
355 12 D355G,
375 12
354 13
376 13 Q376sp, Q376R,
353 13 T353S, T353S,
377 13
352 14
378 14
351 14 S351L,
379 14 S379Y,
350 15
380 15 L380X,