KCNQ1 Variant G297D Detail

We estimate the penetrance of LQTS for KCNQ1 G297D is 17%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. G297D is present in 1 alleles in gnomAD. G297D 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G297D around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.38 0.113 3 0.6 19
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: - 1 1 0
VARIANT FEATURES ALONE: - 10 9 1 -
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.

G297D has 37 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
297 0 G297S, G297D, G297R,
298 3 S298I, S298N,
294 5 V294M,
296 6 F296S, F296L, F296L, F296L,
301 6
281 6 Y281C,
285 7
144 8 T144A,
300 8 A300T, A300S,
302 8 A302V, A302E, A302T,
145 8
299 9
293 9 R293C, R293H,
286 9
318 9
146 10 E146K, E146G, E146Q,
280 10 V280A, V280E,
141 11 V141M,
303 11 L303P,
283 11 A283G, A283T,
143 11 S143F, S143P, S143Y,
282 12 L282P,
277 12 S277L, S277del, S277P, S277W,
231 12 R231C, R231H, R231S,
292 12 G292D,
147 12 Q147R,
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
142 13
140 13 S140G, S140R, S140R, S140R,
278 13 Y278H,
148 13
228 14
227 14
149 14
306 14 G306V, G306R, G306R,
321 14
279 15 F279I,