KCNQ1 Variant I514V Detail

We estimate the penetrance of LQTS for KCNQ1 I514V is 58%. We are unaware of any observations of this variant in individuals. I514V is not present in gnomAD. I514V 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I514V around 58% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.47 0.002 2 0.563 65
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 5 5 -
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.

I514V has 34 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
514 0 I514T,
513 4 T513A, T513S, T513S,
518 5 R518Q, R518G,
517 6 I517T,
512 6
515 6
510 7 H510R, H510Y,
516 7
511 7 R511Q, R511W,
392 7 W392R, W392R, W392ins,
384 8
380 10 R380S, R380S, R380G,
521 10
381 10 C381Y,
520 10 M520R,
394 10 I394L,
391 10 T391A, T391I,
519 10 R519H, R519C,
509 10 H509Q, H509Q, H509R,
508 10 E508G,
383 11
387 11 P387T,
385 12 E385K,
393 12 K393N,
389 12 S389P,
377 12
386 13 N386K, N386K,
379 14 W379R, W379R, W379C, W379C, W379G,
378 14 A378T,
522 14 Y522S,
390 14
523 14
388 14 D388H, D388N,
382 15