KCNQ1 Variant L406P Detail

We estimate the penetrance of LQTS for KCNQ1 L406P is 23%. We are unaware of any observations of this variant in individuals. L406P is not present in gnomAD. L406P has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L406P around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.16 0.004 3 0.634 25
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 8 2 -
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.

L406P 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
406 0
405 4
407 4
404 5
408 5 P408A,
403 7 H403P,
409 7
402 8
410 8
401 8 R401W, R401Q,
411 8
400 9
412 9 P412S,
399 10 A399S, A399V, A399G,
413 10 K413R,
398 11 K398R,
414 11
397 11 R397W, R397Q, R397G,
415 11
396 12
416 12 V416M,
395 13 Y395C,
417 13 V417M,
394 13 I394L,
418 13 V418I,
393 14 K393N,
419 14
392 14 W392R, W392R, W392ins,
420 14 K420E, K420N, K420N,
391 15 T391A, T391I,
421 15 K421N, K421N,