KCNQ1 Variant C331G Detail

We estimate the penetrance of LQTS for KCNQ1 C331G is 41%. We are unaware of any observations of this variant in individuals. C331G is not present in gnomAD. C331G 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C331G around 41% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-10.05 0.13 -1 0.797 43
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
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.

C331G has 33 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 0
330 4
329 6 A329T,
328 6 I328del,
327 6 T327A, T327S, T327S,
325 9 G325R, G325R, G325E, G325W,
279 10 F279I,
324 10
326 10
332 12
333 12
323 12
334 12 V334A,
336 13 A336S,
320 13 P320H, P320A, P320S,
310 13 V310I,
276 13 S276del,
335 13 F335L, F335L, F335L,
273 13 L273F, L273V, L273R,
306 13 G306V, G306R, G306R,
309 13 T309I, T309R,
278 13 Y278H,
307 13 V307L, V307L,
272 13 G272D, G272S, G272V,
322 14 T322M, T322A, T322K,
283 14 A283G, A283T,
340 14 F340del, F340L, F340L, F340L, F340S,
277 14 S277L, S277del, S277P, S277W,
269 14 G269D, G269S, G269del,
282 14 L282P,
270 15 F270S,
308 15 V308F,
274 15 I274V,