KCNH2 Variant D346A Detail

We estimate the penetrance of LQTS for KCNH2 D346A is 9%. We are unaware of any observations of this variant in individuals. D346A is not present in gnomAD. D346A 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 D346A around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.622 0.613 -2 0.701 0
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.

D346A 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
346 0 D346E, D346N, D346Y, D346E,
345 4 G345S,
347 4 P347S,
344 5
348 5
343 7 L343fsX,
349 7
342 8 D342X, D342A, D342V,
350 8
341 8
351 8 S351L,
340 9 F340L, F340L, F340L,
352 9
339 10
353 10 T353S, T353S,
338 11
354 11
337 11 T337S, T337X, T337S,
355 11 D355G,
336 12
356 12 R356C, R356H,
335 13 Q335X,
357 13 E357D, E357D,
334 13 P334L,
358 13
333 14
359 14 I359V,
332 14
360 14
331 15 S331T, S331N,
361 15