KCNH2 Variant P334L Detail

We estimate the penetrance of LQTS for KCNH2 P334L is 63%. This variant was found in a total of 5 carriers in 2 papers or gnomAD, 4 had LQTS. P334L is not present in gnomAD. P334L 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 P334L around 63% (9/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.767 0.974 -3 0.82 54
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
Japan Cohort 2020 2 0 2
France Cohort 2020 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 5 1 4 -
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.

P334L 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
334 0 P334L,
333 4
335 4 Q335X,
332 5
336 5
331 7 S331T, S331N,
337 7 T337S, T337S, T337X,
330 8 I330V,
338 8
329 8
339 8
328 9 R328H, R328C, R328fsX,
340 9 F340L, F340L, F340L,
327 10 Y327H,
341 10
326 11 R326C, R326fsX, R326H,
342 11 D342X, D342A, D342V,
325 11 V325M,
343 11 L343fsX,
324 12 L324L,
344 12
323 13 D323E, D323E, D323N,
345 13 G345S,
322 13
346 13 D346E, D346Y, D346N, D346E,
321 14 D321Y,
347 14 P347S,
320 14 S320L, S320X, S320W,
348 14
319 15 T319T,
349 15