KCNH2 Variant A233S Detail

We estimate the penetrance of LQTS for KCNH2 A233S is 1%. This variant was found in a total of 69 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. A233S is present in 69 alleles in gnomAD. A233S has not been functionally characterized. This residue is located in a Mild_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 A233S around 1% (0/79).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.699 0.23 1 0.32 12
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: - 69 18 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.

A233S 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
233 0 A233S,
232 4 R232P, R232C,
234 4 L234Del,
231 5
235 5
230 7 E230D, E230D,
236 7 G236V,
229 8 E229X,
237 8
228 8 A228X, A228V, A228T, A228P,
238 8 G238R, G238D, G238S,
227 9
239 9 S239X, S239P,
226 10
240 10 P240L,
225 11
241 11 P241fsX, P241L, P241S,
224 11
242 11 R242X, R242C,
223 12
243 12 S243R, S243X, S243R, S243R,
222 13 V222L, V222L,
244 13 A244G, A244E,
221 13
245 13 P245R,
220 14
246 14
219 14 D219V,
247 14 Q247X, Q247R,
218 15
248 15