KCNQ1 Variant M480T Detail

We estimate the penetrance of LQTS for KCNQ1 M480T is 18%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. M480T is present in 1 alleles in gnomAD. M480T 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M480T around 18% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.49 0.002 0 0.441 18
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: - 1 1 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.

M480T 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
480 0 M480T,
479 4 F479L, F479L, F479L,
481 4
478 5 H478Y,
482 5 T482N, T482A, T482S, T482S,
477 7 P477L, P477T,
483 7
476 8 M476L, M476L, M476V,
484 8
475 8
485 8 F485S,
474 9
486 9 A486T,
473 10 E473Q,
487 10 E487K,
472 11 L472P,
488 11 D488E, D488E,
471 11
489 11
470 12
490 12
469 13
491 13
468 13 S468G, S468N,
492 13 L492ins,
467 14 K467R,
493 14 G493A,
466 14
494 14
465 15
495 15 T495S, T495S, T495A,