KCNQ1 Variant L572M Detail

We estimate the penetrance of LQTS for KCNQ1 L572M is 42%. We are unaware of any observations of this variant in individuals. L572M is not present in gnomAD. L572M 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 L572M around 42% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.05 0.425 2 0.598 49
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 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.

L572M 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
572 0
571 4 S571L, S571P,
573 4 F573L, F573L, F573L,
570 5 P570L,
574 5 I574V,
569 7 K569E,
575 7
568 8 G568R, G568R, G568E,
576 8 V576I,
567 8 I567T, I567S,
577 8
566 9 S566F, S566Y, S566P,
578 9 E578K, E578V,
565 10
579 10
564 11 D564H, D564N,
580 11 S580G, S580N,
563 11
581 11
562 12 R562M, R562S, R562S,
582 12
561 13
583 13 R583H, R583C, R583G,
560 13
584 13 G584S,
559 14 L559P,
585 14 S585N,
558 14
586 14 N586D,
557 15 K557E,
587 15 T587M, T587R,