KCNH2 Variant I336N Detail

We estimate the penetrance of LQTS for KCNH2 I336N is 15%. We are unaware of any observations of this variant in individuals. I336N is not present in gnomAD. I336N has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I336N around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.067 0.982 -3 0.787 12
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: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

I336N 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
336 0
335 4 Q335X,
337 4 T337S, T337S, T337X,
334 5 P334L,
338 5
333 7
339 7
332 8
340 8 F340L, F340L, F340L,
331 8 S331N, S331T,
341 8
330 9 I330V,
342 9 D342V, D342X, D342A,
329 10
343 10 L343fsX,
328 11 R328C, R328fsX, R328H,
344 11
327 11 Y327H,
345 11 G345S,
326 12 R326C, R326fsX, R326H,
346 12 D346Y, D346N, D346E, D346E,
325 13 V325M,
347 13 P347S,
324 13 L324L,
348 13
323 14 D323E, D323E, D323N,
349 14
322 14
350 14
321 15 D321Y,
351 15 S351L,