KCNQ1 Variant M476L Detail

We estimate the penetrance of LQTS for KCNQ1 M476L is 45%. This variant was found in a total of 1 carriers in 2 papers or gnomAD, 1 had LQTS. M476L is not present in gnomAD. M476L 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M476L around 45% (4/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.37 0.001 0 0.391 44
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
32893267 2020 1 None 1 None
17192539 2006 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 7 3 -
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.

M476L 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
476 0 M476L, M476L, M476V,
475 4
477 4 P477L, P477T,
474 5
478 5 H478Y,
473 7 E473Q,
479 7 F479L, F479L, F479L,
472 8 L472P,
480 8 M480T,
471 8
481 8
470 9
482 9 T482N, T482A, T482S, T482S,
469 10
483 10
468 11 S468G, S468N,
484 11
467 11 K467R,
485 11 F485S,
466 12
486 12 A486T,
465 13
487 13 E487K,
464 13 S464P,
488 13 D488E, D488E,
463 14 S463T,
489 14
462 14
490 14
461 15
491 15