KCNQ1 Variant L471R Detail

We estimate the penetrance of LQTS for KCNQ1 L471R is 11%. We are unaware of any observations of this variant in individuals. L471R is not present in gnomAD. L471R has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L471R around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.03 0.853 -2 0.679 7
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 9 1 -
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.

L471R 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
471 0
470 4
472 4 L472P,
469 5
473 5 E473Q,
468 7 S468G, S468N,
474 7
467 8 K467R,
475 8
466 8
476 8 M476L, M476L, M476V,
465 9
477 9 P477L, P477T,
464 10 S464P,
478 10 H478Y,
463 11 S463T,
479 11 F479L, F479L, F479L,
462 11
480 11 M480T,
461 12
481 12
460 13 G460S, G460D, G460C,
482 13 T482N, T482A, T482S, T482S,
459 13 D459N, D459V,
483 13
458 14
484 14
457 14
485 14 F485S,
456 15 F456L, F456L, F456L,
486 15 A486T,