KCNQ1 Variant S330T Detail

We estimate the penetrance of LQTS for KCNQ1 S330T is 31%. We are unaware of any observations of this variant in individuals. S330T is not present in gnomAD. S330T 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S330T around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.79 0.988 0 0.882 34
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.

S330T 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
331 4
327 6 T327A, T327S, T327S,
326 8
329 10 A329T,
333 10
330 10
324 10
309 11 T309I, T309R,
310 11 V310I,
306 11 G306V, G306R, G306R,
307 11 V307L, V307L,
332 12
323 12
336 12 A336S,
276 12 S276del,
328 12 I328del,
273 12 L273F, L273V, L273R,
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
322 12 T322M, T322A, T322K,
335 13 F335L, F335L, F335L,
334 13 V334A,
277 13 S277L, S277del, S277P, S277W,
340 13 F340del, F340L, F340L, F340L, F340S,
272 14 G272D, G272S, G272V,
325 14 G325R, G325R, G325E, G325W,
280 14 V280A, V280E,
304 14 W304R, W304R,
283 14 A283G, A283T,
320 14 P320H, P320A, P320S,
303 14 L303P,
302 14 A302V, A302E, A302T,
337 14
269 15 G269D, G269S, G269del,
321 15
270 15 F270S,
338 15 S338F,
274 15 I274V,