KCNH2 Variant L349S Detail

We estimate the penetrance of LQTS for KCNH2 L349S is 9%. We are unaware of any observations of this variant in individuals. L349S is not present in gnomAD. L349S 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 L349S around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.825 0.23 -1 0.586 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.

L349S 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
349 0
348 4
350 4
347 5 P347S,
351 5 S351L,
346 7 D346N, D346E, D346E, D346Y,
352 7
345 8 G345S,
353 8 T353S, T353S,
344 8
354 8
343 9 L343fsX,
355 9 D355G,
342 10 D342V, D342A, D342X,
356 10 R356C, R356H,
341 11
357 11 E357D, E357D,
340 11 F340L, F340L, F340L,
358 11
339 12
359 12 I359V,
338 13
360 13
337 13 T337S, T337S, T337X,
361 13
336 14
362 14
335 14 Q335X,
363 14 I363X,
334 15 P334L,
364 15 K364X,