KCNH2 Variant P352L Detail

We estimate the penetrance of LQTS for KCNH2 P352L is 10%. We are unaware of any observations of this variant in individuals. P352L is not present in gnomAD. P352L 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P352L around 10% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.353 0.945 -3 0.798 1
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.

P352L 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
352 0
351 4 S351L,
353 4 T353S, T353S,
350 5
354 5
349 7
355 7 D355G,
348 8
356 8 R356C, R356H,
347 8 P347S,
357 8 E357D, E357D,
346 9 D346E, D346Y, D346E, D346N,
358 9
345 10 G345S,
359 10 I359V,
344 11
360 11
343 11 L343fsX,
361 11
342 12 D342A, D342V, D342X,
362 12
341 13
363 13 I363X,
340 13 F340L, F340L, F340L,
364 13 K364X,
339 14
365 14 E365G,
338 14
366 14 R366X, R366Q,
337 15 T337S, T337X, T337S,
367 15 T367S, T367S,