KCNH2 Variant H368Y Detail

We estimate the penetrance of LQTS for KCNH2 H368Y is 7%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. H368Y is present in 1 alleles in gnomAD. H368Y 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 H368Y around 7% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.311 0.994 1 0.674 4
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: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

H368Y 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
368 0 H368Y,
367 4 T367S, T367S,
369 4 N369K, N369K,
366 5 R366Q, R366X,
370 5
365 7 E365G,
371 7
364 8 K364X,
372 8
363 8 I363X,
373 8
362 9
374 9
361 10
375 10
360 11
376 11 Q376R, Q376sp,
359 11 I359V,
377 11
358 12
378 12
357 13 E357D, E357D,
379 13 S379Y,
356 13 R356C, R356H,
380 13 L380X,
355 14 D355G,
381 14
354 14
382 14 A382T,
353 15 T353S, T353S,
383 15