KCNH2 Variant T337N Detail

We estimate the penetrance of LQTS for KCNH2 T337N is 8%. We are unaware of any observations of this variant in individuals. T337N is not present in gnomAD. T337N 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 T337N around 8% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.208 0.984 0 0.711 3
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.

T337N 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
337 0 T337S, T337S, T337X,
336 4
338 4
335 5 Q335X,
339 5
334 7 P334L,
340 7 F340L, F340L, F340L,
333 8
341 8
332 8
342 8 D342V, D342X, D342A,
331 9 S331N, S331T,
343 9 L343fsX,
330 10 I330V,
344 10
329 11
345 11 G345S,
328 11 R328H, R328C, R328fsX,
346 11 D346E, D346Y, D346E, D346N,
327 12 Y327H,
347 12 P347S,
326 13 R326H, R326C, R326fsX,
348 13
325 13 V325M,
349 13
324 14 L324L,
350 14
323 14 D323E, D323E, D323N,
351 14 S351L,
322 15
352 15