KCNQ1 Variant W248R Detail

We estimate the penetrance of LQTS for KCNQ1 W248R is 76%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. W248R is not present in gnomAD. W248R has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W248R around 76% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-13.61 1.0 0 0.887 80
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 LQT1 Other Disease
32893267 2020 1 None 1 None
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
10409658 Oocytes 0 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
10409658 Oocytes None None None

W248R has 42 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. This results from the fact that the functional KV7.1 channel 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
248 0 W248C, W248C, W248R, W248R,
245 5 G245V,
242 5 D242N, D242Y,
247 5 T247I,
246 6
268 7 I268V, I268S,
239 7
249 7 R249S, R249S,
267 8 Y267C,
251 8 L251P, L251Q,
198 8 I198V, I198T,
271 9
264 9
250 9 L250H, L250P,
252 9 G252R,
241 9 V241F, V241I, V241G,
243 9 R243H, R243C, R243P, R243S,
244 9
197 10 P197L,
240 10 H240R, H240P,
201 11 I201del,
265 11 T265I,
269 11 G269D, G269S, G269del,
238 11 M238V, M238L, M238L,
196 11
253 11 S253A, S253P,
272 12 G272D, G272S, G272V,
339 12 F339del, F339S,
236 12 L236Q, L236R,
275 13 F275del,
199 13 S199A,
202 13 D202N, D202H,
270 13 F270S,
200 13
254 13 V254M, V254L, V254L,
335 13 F335L, F335L, F335L,
235 14 I235N,
130 14
115 14 E115A, E115G,
274 14 I274V,
351 15 F351L, F351L, F351L, F351S,
336 15 A336S,