KCNQ1 Variant L374H Detail

We estimate the penetrance of LQTS for KCNQ1 L374H is 62%. This variant was found in a total of 7 carriers in 3 papers or gnomAD, 6 had LQTS. L374H is present in 1 alleles in gnomAD. L374H 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 L374H around 62% (10/17).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.59 1.0 -1 0.973 56
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
31899541 2020 6 None 6 None
23631430 2013 1 None None None
19716085 2009 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 7 1 6
VARIANT FEATURES ALONE: - 10 6 4 -
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.

L374H has 35 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
374 0 L374H, L374F,
373 5 S373P,
375 5
525 5 A525T, A525V,
371 5 A371T,
377 5
522 6 Y522S,
372 6
378 6 A378T,
529 6
370 6 A370V,
526 7 K526Q, K526E,
376 7
524 9 V524G,
528 9
523 9
369 10
530 10
380 10 R380S, R380S, R380G,
521 10
381 10 C381Y,
527 11
379 11 W379R, W379R, W379C, W379C, W379G,
368 11
367 11 Q367H, Q367H,
532 12
533 12 R533W, R533Q,
519 13 R519H, R519C,
518 13 R518Q, R518G,
531 13
382 13
520 13 M520R,
383 14
534 15
517 15 I517T,