KCNH2 Variant S239P Detail

We estimate the penetrance of LQTS for KCNH2 S239P is 9%. This variant was found in a total of 4 carriers in 1 papers or gnomAD (version 4), 2 had LQTS. S239P is present in 1 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 84% of WT with a standard error of 19%; 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. S239P 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S239P around 9% (3/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.513 0.0 3 0.302 50
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
France Cohort 2020 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 4 1 2 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

S239P 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
239 0 S239X, S239P,
238 4 G238R, G238D, G238S,
240 4 P240L,
237 5
241 5 P241fsX, P241L, P241S,
236 7 G236V,
242 7 R242C, R242X,
235 8
243 8 S243X, S243R, S243R, S243R,
234 8 L234Del,
244 8 A244G, A244E,
233 9 A233S,
245 9 P245R,
232 10 R232C, R232P,
246 10
231 11
247 11 Q247X, Q247R,
230 11 E230D, E230D,
248 11
229 12 E229X,
249 12
228 13 A228T, A228V, A228X, A228P,
250 13
227 13
251 13 P251A,
226 14
252 14 R252fsX, R252Q,
225 14
253 14
224 15
254 15 H254Q, H254X, H254Q,