KCNH2 Variant A228V Detail

We estimate the penetrance of LQTS for KCNH2 A228V is 15%. This variant was found in a total of 3 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. A228V is present in 2 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 115% of WT with a standard error of 15%; 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. A228V 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 A228V around 15% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.963 0.002 0 0.324 16
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
22727609 2012 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 3 1 1 -
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.

A228V 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
228 0 A228X, A228V, A228T, A228P,
227 4
229 4 E229X,
226 5
230 5 E230D, E230D,
225 7
231 7
224 8
232 8 R232P, R232C,
223 8
233 8 A233S,
222 9 V222L, V222L,
234 9 L234Del,
221 10
235 10
220 11
236 11 G236V,
219 11 D219V,
237 11
218 12
238 12 G238R, G238D, G238S,
217 13
239 13 S239X, S239P,
216 13 T216A,
240 13 P240L,
215 14 V215G, V215X,
241 14 P241fsX, P241L, P241S,
214 14 E214X,
242 14 R242X, R242C,
213 15 D213G,
243 15 S243R, S243X, S243R, S243R,