KCNQ1 Variant S298T Detail

We estimate the penetrance of LQTS for KCNQ1 S298T is 35%. We are unaware of any observations of this variant in individuals. S298T is not present in gnomAD. S298T has not been functionally characterized. 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S298T around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.37 0.78 3 0.786 41
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 7 3 -
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.

S298T has 46 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
298 0 S298I, S298N,
297 3 G297S, G297D, G297R,
301 4
300 4 A300T, A300S,
144 6 T144A,
299 6
281 6 Y281C,
145 6
302 7 A302V, A302E, A302T,
296 7 F296S, F296L, F296L, F296L,
141 8 V141M,
303 8 L303P,
294 9 V294M,
285 9
143 10 S143F, S143P, S143Y,
142 10
318 10
146 10 E146K, E146G, E146Q,
304 10 W304R, W304R,
277 10 S277L, S277del, S277P, S277W,
140 11 S140G, S140R, S140R, S140R,
231 11 R231C, R231H, R231S,
293 11 R293C, R293H,
147 11 Q147R,
148 11
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
286 12
282 12 L282P,
278 12 Y278H,
306 13 G306V, G306R, G306R,
138 13
149 13
274 14 I274V,
276 14 S276del,
137 14 L137F, L137P,
227 14
228 14
307 14 V307L, V307L,
326 14
279 14 F279I,
273 15 L273F, L273V, L273R,
139 15
321 15
322 15 T322M, T322A, T322K,
308 15 V308F,
320 15 P320H, P320A, P320S,