KCNH2 Variant S331N Detail

We estimate the penetrance of LQTS for KCNH2 S331N is 5%. This variant was found in a total of 4 carriers in 1 papers or gnomAD, 0 had LQTS. S331N is present in 1 alleles in gnomAD. S331N 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 S331N around 5% (0/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.401 0.041 3 0.253 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
Italy Cohort 2020 3 3 0
LITERATURE, COHORT, AND GNOMAD: - 4 4 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.

S331N 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
331 0 S331T, S331N,
330 4 I330V,
332 4
329 5
333 5
328 7 R328H, R328C, R328fsX,
334 7 P334L,
327 8 Y327H,
335 8 Q335X,
326 8 R326fsX, R326H, R326C,
336 8
325 9 V325M,
337 9 T337S, T337X, T337S,
324 10 L324L,
338 10
323 11 D323N, D323E, D323E,
339 11
322 11
340 11 F340L, F340L, F340L,
321 12 D321Y,
341 12
320 13 S320W, S320X, S320L,
342 13 D342V, D342X, D342A,
319 13 T319T,
343 13 L343fsX,
318 14
344 14
317 14 N317S,
345 14 G345S,
316 15
346 15 D346E, D346Y, D346E, D346N,