KCNQ1 Variant S333A Detail

We estimate the penetrance of LQTS for KCNQ1 S333A is 72%. We are unaware of any observations of this variant in individuals. S333A is not present in gnomAD. S333A 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S333A around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.75 0.541 1 0.767 82
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 3 7 -
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.

S333A has 23 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
328 9 I328del,
306 11 G306V, G306R, G306R,
325 11 G325R, G325R, G325E, G325W,
273 12 L273F, L273V, L273R,
279 12 F279I,
312 12 T312del, T312I,
270 12 F270S,
313 13
304 13 W304R, W304R,
269 13 G269D, G269S, G269del,
311 13 T311A, T311I,
333 14
266 14 L266P,
272 14 G272D, G272S, G272V,
324 14
336 14 A336S,
331 14
314 14 G314S, G314D, G314C, G314del,
276 14 S276del,
303 14 L303P,
278 14 Y278H,
332 15
277 15 S277L, S277del, S277P, S277W,