KCNQ1 Variant I517N Detail

We estimate the penetrance of LQTS for KCNQ1 I517N is 73%. We are unaware of any observations of this variant in individuals. I517N is not present in gnomAD. I517N 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 I517N around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.44 0.992 -3 0.913 79
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.

I517N has 31 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
517 0 I517T,
516 4
520 5 M520R,
514 6 I514T,
521 6
518 6 R518Q, R518G,
513 6 T513A, T513S, T513S,
515 8
519 8 R519H, R519C,
512 9
380 9 R380S, R380S, R380G,
381 10 C381Y,
523 10
377 10
524 11 V524G,
522 11 Y522S,
384 11
510 11 H510R, H510Y,
392 12 W392R, W392R, W392ins,
511 12 R511Q, R511W,
525 13 A525T, A525V,
394 13 I394L,
378 13 A378T,
383 13
391 13 T391A, T391I,
509 14 H509Q, H509Q, H509R,
385 14 E385K,
376 14
373 14 S373P,
374 15 L374H, L374F,
379 15 W379R, W379R, W379C, W379C, W379G,