KCNQ1 Variant I328F Detail

We estimate the penetrance of LQTS for KCNQ1 I328F is 70%. We are unaware of any observations of this variant in individuals. I328F is not present in gnomAD. I328F 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I328F around 70% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.57 0.989 6 0.862 74
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 4 6 -
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.

I328F has 38 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 0 I328del,
325 4 G325R, G325R, G325E, G325W,
329 4 A329T,
327 5 T327A, T327S, T327S,
331 6
332 6
279 6 F279I,
324 6
280 7 V280A, V280E,
283 8 A283G, A283T,
333 9
320 9 P320H, P320A, P320S,
322 9 T322M, T322A, T322K,
323 9
282 9 L282P,
278 9 Y278H,
284 10 E284K,
275 11 F275del,
335 11 F335L, F335L, F335L,
281 12 Y281C,
319 12 V319L, V319L,
321 12
307 13 V307L, V307L,
304 13 W304R, W304R,
306 13 G306V, G306R, G306R,
308 14 V308F,
232 14
303 14 L303P,
285 14
287 14 A287E, A287T, A287S,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
302 15 A302V, A302E, A302T,
309 15 T309I, T309R,
273 15 L273F, L273V, L273R,
277 15 S277L, S277del, S277P, S277W,
311 15 T311A, T311I,
330 15
310 15 V310I,