KCNQ1 Variant P197T Detail

We estimate the penetrance of LQTS for KCNQ1 P197T is 27%. We are unaware of any observations of this variant in individuals. P197T is not present in gnomAD. P197T has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P197T around 27% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.38 0.998 0 0.962 31
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

P197T has 36 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
197 0 P197L,
196 4
198 5 I198V, I198T,
200 5
199 6 S199A,
201 6 I201del,
194 8 A194P, A194T,
195 9 R195Q, R195W,
202 9 D202N, D202H,
245 9 G245V,
248 10 W248C, W248C, W248R, W248R,
193 10 F193L, F193L, F193L,
244 10
243 10 R243H, R243C, R243P, R243S,
204 10 I204M, I204F,
239 11
203 11 L203P,
240 11 H240R, H240P,
242 11 D242N, D242Y,
249 11 R249S, R249S,
171 12
236 12 L236Q, L236R,
192 12 R192C, R192H,
246 12
115 13 E115A, E115G,
205 13 V205M,
191 13
184 13 Y184S, Y184C, Y184D, Y184H,
174 13 R174H, R174C, R174L,
247 14 T247I,
241 14 V241F, V241I, V241G,
183 14 K183R,
175 14 L175I,
189 14 G189R, G189R, G189E,
252 15 G252R,
206 15 V206L,