KCNH2 Variant P298L Detail

We estimate the penetrance of LQTS for KCNH2 P298L is 6%. This variant was found in a total of 3 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. P298L is present in 3 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 83% of WT with a standard error of 13%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. P298L 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 P298L around 6% (0/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.848 0.011 0 0.458 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
LITERATURE, COHORT, AND GNOMAD: - 3 0 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.

P298L 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
298 0 P298X,
297 4 P297S,
299 4
296 5 L296fsX,
300 5
295 7 V295fsX,
301 7
294 8
302 8 H302H, H302X, H302fsX,
293 8
303 8
292 9
304 9 S304R, S304R, S304R,
291 10
305 10
290 11
306 11 G306W,
289 11 E289K,
307 11 A307P,
288 12
308 12 M308T, M308I, M308I, M308I, M308V, M308R,
287 13 D287fsX,
309 13 H309Q, H309Y, H309Q,
286 13 D286X,
310 13 P310X, P310L,
285 14 A285fsX, A285V,
311 14 L311R,
284 14 S284X,
312 14 R312Del, R312H, R312C,
283 15
313 15